Darrel Cook

Increasing incidence of HIV infections among young gay and biseuxal men in Vancouver

Since the beginning of the HIV epidemic in north America, the majority of HIV infections have occurred among men who engage in sexual relations with other men. As the HIV epidemic enters its third decade, gay and bisexual men continue to have among the highest rates of HIV infection. Previous studies have highlighted the decline in the incidence of HIV and risk behaviour among gay and bisexual men. However, several studies have suggested that young gay and bisexual men continue to engage in unprotected sexual behaviours and are at continued risk of HIV infection. Recent reports in the media and research literature have indicated an increase in the incidence of HIV among gay and bisexual individuals in many of the worlds major cities. The purpose of this study was to determine trends in HIV incidence using data from a prospective cohort of young gay and bisexual men.

Primary cervical cancer screening with HPV testing compared with liquid-based cytology: results of round 1 of a randomised controlled trial – the HPV FOCAL Study

Background:Round 1 data of human papillomavirus (HPV) FOCAL, a three-arm, randomised trial, which aims to establish the efficacy of HPV DNA testing as a primary screen for cervical cancer, are presented.Methods:The three arms are: Control arm – liquid based cytology with atypical squamous cells of unknown significance (ASC-US) triage with hrHPV testing; Intervention Arm – hrHPV at entry with liquid-based cytology (LBC) triage of hrHPV positives, with exit screen at 4 years; Safety check arm – hrHPV at entry with LBC triage of hrHPV positives with exit screen at 2 years.Results:A total of 6154 women were randomised to the control arm and 12 494 to the HPV arms (intervention and safety check). In the HPV arm, the baseline cervical intraepithelial neoplasia (CIN)2+ and CIN3+ rate was 9.2/1000 (95%CI; 7.4, 10.9) and 4.8/1000 (95%CI; 3.6, 6.1), which increased to 16.1/1000 (95%CI 13.2, 18.9) for CIN2+ and to 8.0/1000 (95%CI; 5.9, 10.0) for CIN3+ after subsequent screening of HPV-DNA-positive/cytology-negative women. Detection rate in the control arm remained unchanged after subsequent screening of ASC-US-positive/hrHPV DNA-negative women at 11.0/1000 for CIN2+ and 5.0/1000 for CIN3+.Conclusion:After subsequent screening of women who were either hrHPV positive/cytology negative or ASC-US positive/HPV negative, women randomised to the HPV arms had increased CIN2+ detection compared with women randomised to the cytology arm.

A randomized controlled trial of Human Papillomavirus (HPV) testing for cervical cancer screening: trial design and preliminary results (HPV FOCAL Trial)

BackgroundIn the HPV FOCAL trial, we will establish the efficacy of hr-HPV DNA testing as a stand-alone screening test followed by liquid based cytology (LBC) triage of hr-HPV-positive women compared to LBC followed by hr-HPV triage with ≥ CIN3 as the outcome.Methods/DesignHPV-FOCAL is a randomized, controlled, three-armed study over a four year period conducted in British Columbia. It will recruit 33,000 women aged 25-65 through the provinces population based cervical cancer screening program. Control arm: LBC at entry and two years, and combined LBC and hr-HPV at four years among those with initial negative results and hr-HPV triage of ASCUS cases; Two Year Safety Check arm: hr-HPV at entry and LBC at two years in those with initial negative results with LBC triage of hr-HPV positives; Four Year Intervention Arm: hr-HPV at entry and combined hr-HPV and LBC at four years among those with initial negative results with LBC triage of hr-HPV positive casesDiscussionTo date, 6150 participants have a completed sample and epidemiologic questionnaire. Of the 2019 women enrolled in the control arm, 1908 (94.5%) were cytology negative. Women aged 25-29 had the highest rates of HSIL (1.4%). In the safety arm 92.2% of women were hr-HPV negative, with the highest rate of hr-HPV positivity found in 25-29 year old women (23.5%). Similar results were obtained in the intervention arm HPV FOCAL is the first randomized trial in North America to examine hr-HPV testing as the primary screen for cervical cancer within a population-based cervical cancer screening program.Trial RegistrationInternational Standard Randomised Controlled Trial Number Register, ISRCTN79347302

Antenatal Seroprevalence of Herpes Simplex Virus Type 2 (HSV-2) in Canadian Women HSV-2 Prevalence Increases Throughout the Reproductive Years

Background Thisstudy sought to provide the first population estimates of herpes simplex type2 (HSV-2) seroprevalence inCanada. Goal Tomeasure the antenatal seroprevalence of HSV-2 antibodies in reproductive agewomen. StudyDesign An anonymous unlinked seroprevalence study usedstored sera collected from pregnant women in British Columbia during 1999.Randomized sampling within age strata selected a total of 1215 subjects, ages15 to 44 years. Serologic testing used the Gull Meridian Test. Overallprevalence was directly standardized to the 1999 Canadian femalepopulation. Results Theage-adjusted prevalence for HSV-2 was 17.3% (95% CI, 15.2–19.4).Prevalence ranged from 7.1% (ages, 15–19 years) to 28.1% (ages,40–44 years), with the largest increases after the age of 24years. Conclusions TheHSV-2 seroprevalence among pregnant women in British Columbia is similar tothat in the United States and other countries. Seroprevalence continues torise through the later reproductive years. This observation may relate tocontinued transmission, an age cohort effect, orboth.

Human Papillomavirus 16 (HPV 16) and HPV 18 Antibody Responses Measured by Pseudovirus Neutralization and Competitive Luminex Assays in a Two- versus Three-Dose HPV Vaccine Trial

ABSTRACT Human papillomavirus 16 (HPV 16) and HPV 18 antibody responses in a 2- versus 3-dose HPV vaccine (Gardasil) trial were measured by a pseudovirus neutralizing antibody (PsV NAb) assay and by the Merck competitive Luminex immunoassay (cLIA). Eight hundred twenty-four female subjects assigned to three dosing regimens (group 1, 9 to 13 years old; 2 doses, months 0 and 6 [n = 259]; group 2, 9 to 13 years old; 3 doses, months 0, 2, and 6 [n = 260]; group 3, 16 to 26 years old; 3 doses, months 0, 2, and 6 [n = 305]) had postvaccine responses assessed 1 month after the last dose. Of 791 subjects with baseline and 7-month sera, 15 (1.9%) and 9 (1.1%) were baseline seropositive for HPV 16 and HPV 18, respectively. All baseline-seronegative vaccinees seroconverted to both HPV 16 and HPV 18. Mean anti-HPV 16 levels were similar for groups 1 and 2 (for PsV NAb, P = 0.675; for cLIA, P = 0.874), and levels for both groups 1 and 2 were approximately 2-fold higher than that for group 3 (for PsV NAb and cLIA, P < 0.001). Mean anti-HPV 18 levels were approximately 1.4-fold lower in group 1 than in group 2 (for PsV, NAb P = 0.013; for cLIA, P = 0.001), and levels for both groups 1 and 2 were approximately 2.0- to 2.5-fold higher than that for group 3 (for PsV NAb and cLIA, P < 0.001). Pearson correlation coefficients for the assays were 0.672 for HPV 16 and 0.905 for HPV 18. Most of the discordant results were observed at lower cLIA signals. These results suggest that the PsV NAb assay could be a suitable alternative to cLIA for the measurement of postvaccine antibody responses.

Genetic Diversity as a Marker for Timing Infection in HIV-Infected Patients: Evaluation of a 6-Month Window and Comparison With BED

BACKGROUND It has been reported that the increase in human immunodeficiency virus (HIV) sequence diversity in drug resistance surveillance specimens may be used to classify the duration of HIV infection as <1 or >1 year. We describe a mixed base classifier (MBC) optimized to categorize the duration of subtype B infections as <6 or >6 months on the basis of sequences for drug resistance surveillance specimens and compared MBC findings with those of serologic methods. METHODS The behavior of the MBC was examined across a range of thresholds for calling mixed bases. MBC performance was then evaluated using either complete pol sequences or sites reflecting evolutionary pressures (HLA selection sites, sites that increased in entropy over the course of infection, and codon positions). RESULTS The MBC performance was optimal when secondary peaks on the sequencing chromatogram accounted for at least 15% of the area of primary peaks. A cutoff of <0.45% mixed bases in the pol region best identified recent infections (sensitivity = 82.7%, specificity = 78.8%), with improvement achieved by analyzing only sites that increased in entropy. CONCLUSIONS In an extended data set of 1354 specimens classified by BED, the optimized MBC performed significantly better than a simple MBC (agreement, 68.98% vs 67.13%). If further validated, the MBC may prove beneficial for detecting recent infection and estimating the incidence of HIV infection.

GBV-C/hepatitis G virus infection and non-Hodgkin lymphoma: a case control study.

We investigated whether there was an association between GBV‐C viremia and the development of non‐Hodgkin lymphoma (NHL) in 553 NHL cases and 438 controls from British Columbia, Canada. Cases were aged 20–79, diagnosed between March 2000 and February 2004, and resident in Greater Vancouver or Victoria. Cases and controls were tested for GBV‐C RNA by RT‐PCR and positive samples were genotyped. Overall, GBV‐C RNA was detected in 4.5% of NHL cases vs. 1.8% of controls [adjusted odds ratio (OR) = 2.72, 95% confidence interval (CI) = 1.22–6.69]. The association between GBV‐C RNA detection and NHL remained even after individuals with a history of prior transfusion, injection drug use and hepatitis C virus sero‐positivity were excluded. GBV‐C viremia showed the strongest association with diffuse large B cell lymphoma (adjusted OR = 5.18, 95% CI = 2.06–13.71). Genotyping was performed on 29/33 GBV‐C RNA positive individuals; genotypes 2a (n = 22); 2b (n = 5) and 3 (n = 2) were identified, consistent with the distribution of genotypes found in North America. This is the largest case‐control study to date associating GBV‐C viremia and NHL risk. As GBV‐C is known to be transmitted through blood products this may have important implications for blood safety.

Long-term effect of sustained virological response on hepatocellular carcinoma in patients with hepatitis C in Canada

BACKGROUND & AIMS Evidence is limited on hepatocellular carcinoma (HCC) risk after sustained virological response (SVR) to interferon-based treatment of hepatitis C virus (HCV) infection. We evaluated the effect of SVR on the risk of HCC and estimated its incidence in post-SVR HCV patients from a large population-based Canadian cohort. METHODS The British Columbia Hepatitis Testers Cohort includes individuals tested for HCV between 1990-2013 linked with data on their medical visits, hospitalizations, cancers, prescription drugs and mortality. Patients receiving interferon-based HCV treatments were followed from the end of treatment to HCC diagnosis, death or December 31, 2012. We examined HCC risk among those who did and did not achieve SVR using multivariable proportional hazard models with the Fine and Gray modification for competing risks. RESULTS Of 8147 individuals who received HCV treatment and were eligible for analysis, 4663 (57%) achieved SVR and 3484 (43%) did not. Each group was followed for a median of 5.6years (range: 0.5-12.9) for an HCC incidence rate of 1.1/1000 person-years (PY) among the SVR and 7.2/1000 PY among the no SVR group. The HCC incidence rate was higher among those with cirrhosis (SVR: 6.4, no SVR: 21.0/1000 PY). In the multivariable model, SVR was associated with a lower HCC risk (subdistribution hazard ratio [SHR]=0.20, 95% CI: 0.13-0.3), while cirrhosis (SHR=2.61, 95% CI: 1.68-4.04), age ⩾50years, being male and genotype 3 infection were associated with a higher HCC risk. Among those who achieved SVR, cirrhosis, age ⩾50years and being male were associated with a higher HCC risk. CONCLUSION SVR after interferon-based treatment substantially reduces but does not eliminate HCC risk, which is markedly higher among those with cirrhosis and age ⩾50years at treatment initiation. Treatment of patients at an advanced fibrosis stage with new highly effective drugs will warrant continued surveillance for HCC post-SVR. LAY SUMMARY We assessed the effect of successful hepatitis C treatment with older interferon-based treatment on the occurrence of liver cancer (hepatocellular carcinoma) and found that successful treatment prevents liver cancer. However, more people with cirrhosis and older age continued to develop liver cancer after successful treatment. Thus, treatment with new drugs among those with cirrhosis will require continued monitoring for liver cancer.

HPV for cervical cancer screening (HPV FOCAL): Complete Round 1 results of a randomized trial comparing HPV‐based primary screening to liquid‐based cytology for cervical cancer

Complete Round 1 data (baseline and 12‐month follow‐up) for HPV FOCAL, a randomized trial establishing the efficacy of HPV DNA testing with cytology triage as a primary screen for cervical cancer are presented. Women were randomized to one of three arms: Control arm – Baseline liquid‐based cytology (LBC) with ASCUS results triaged with HPV testing; Intervention and Safety arms – Baseline HPV with LBC triage for HPV positives. Results are presented for 15,744 women allocated to the HPV (intervention and safety combined) and 9,408 to the control arms. For all age cohorts, the CIN3+ detection rate was higher in the HPV (7.5/1,000; 95%CI: 6.2, 8.9) compared to the control arm (4.6/1,000; 95%CI: 3.4, 6.2). The CIN2+ detection rates were also significantly higher in the HPV (16.5/1,000; 95%CI: 14.6, 18.6) vs. the control arm (10.1/1,000; 95%CI: 8.3, 12.4). In women ≥35 years, the overall detection rates for CIN2+ and CIN3+ were higher in the HPV vs. the control arm (CIN2+:10.0/1,000 vs. 5.2/1,000; CIN3+: 4.2/1,000 vs. 2.2/1,000 respectively, with a statistically significant difference for CIN2+). HPV testing detected significantly more CIN2+ in women 25–29 compared to LBC (63.7/1,000; 95%CI: 51.9, 78.0 vs. 32.4/1,000; 95%CI: 22.3, 46.8). HPV testing resulted in significantly higher colposcopy referral rates for all age cohorts (HPV: 58.9/1,000; 95%CI: 55.4, 62.7 vs. control: 30.9/1,000; 95%CI: 27.6, 34.6). At completion of Round 1 HPV‐based cervical cancer screening in a population‐based program resulted in greater CIN2+ detection of across all age cohorts compared to LBC screening.

The Population Level Cascade of Care for Hepatitis C in British Columbia, Canada: The BC Hepatitis Testers Cohort (BC-HTC)

Background Population-level monitoring of hepatitis C virus (HCV) infected people across the cascade of care identifies gaps in access and engagement in care and treatment. We characterized a population-level cascade of care for HCV in British Columbia (BC), Canada and identified factors associated with leakage at each stage. Methods The BC Hepatitis Testers Cohort (BC-HTC) includes 1.5 million individuals tested for HCV, HIV, reported cases of hepatitis B, and active tuberculosis in BC from 1990 to 2013 linked to medical visits, hospitalizations, cancers, prescription drugs and mortality data. We defined six HCV cascade of care stages: 1) estimated population prevalence; 2) HCV diagnosed; 3) HCV RNA tested; 4) genotyped; 5) initiated treatment; and 6) achieved sustained virologic response (SVR). Results We estimated that 73,203 people were HCV antibody positive in BC in 2012 (undiagnosed: 18,301, 25%; diagnosed: 54,902, 75%). Of these, 56%(40,656) had HCV RNA testing; 34%(26,300) were genotyped; 12%( 8532 ) had received interferon-based therapy and 7%(5197) had SVR. Males, older birth cohorts, and HBV coinfected were less likely to undergo HCV RNA testing. Among those with chronic HCV infection, 32% had received liver-related care. Retention in liver care was more likely in those with HIV, cirrhosis, and drug/alcohol use and less likely in males and HBV coinfected. Conclusions Although there are gaps in HCV RNA testing and genotyping after HCV diagnosis, the major gap in the cascade of care was low treatment initiation. People with comorbidities progressed through the cascade of testing and care but few received treatment.