Danielle Rouleau

Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males.

BACKGROUND Infection with human papillomavirus (HPV) and diseases caused by HPV are common in boys and men. We report on the safety of a quadrivalent vaccine (active against HPV types 6, 11, 16, and 18) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men. METHODS We enrolled 4065 healthy boys and men 16 to 26 years of age, from 18 countries in a randomized, placebo-controlled, double-blind trial. The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions related to HPV-6, 11, 16, or 18. Efficacy analyses were conducted in a per-protocol population, in which subjects received all three vaccinations and were negative for relevant HPV types at enrollment, and in an intention-to-treat population, in which subjects received vaccine or placebo, regardless of baseline HPV status. RESULTS In the intention-to-treat population, 36 external genital lesions were seen in the vaccine group as compared with 89 in the placebo group, for an observed efficacy of 60.2% (95% confidence interval [CI], 40.8 to 73.8); the efficacy was 65.5% (95% CI, 45.8 to 78.6) for lesions related to HPV-6, 11, 16, or 18. In the per-protocol population, efficacy against lesions related to HPV-6, 11, 16, or 18 was 90.4% (95% CI, 69.2 to 98.1). Efficacy with respect to persistent infection with HPV-6, 11, 16, or 18 and detection of related DNA at any time was 47.8% (95% CI, 36.0 to 57.6) and 27.1% (95% CI, 16.6 to 36.3), respectively, in the intention-to-treat population and 85.6% (97.5% CI, 73.4 to 92.9) and 44.7% (95% CI, 31.5 to 55.6) in the per-protocol population. Injection-site pain was significantly more frequent among subjects receiving quadrivalent HPV vaccine than among those receiving placebo (57% vs. 51%, P<0.001). CONCLUSIONS Quadrivalent HPV vaccine prevents infection with HPV-6, 11, 16, and 18 and the development of related external genital lesions in males 16 to 26 years of age. (Funded by Merck and others; ClinicalTrials.gov number, NCT00090285.).

High Rates of Forward Transmission Events after Acute/Early HIV-1 Infection

BACKGROUND A population-based phylogenetic approach was used to characterize human immunodeficiency virus (HIV)-transmission dynamics in Quebec. METHODS HIV-1 pol sequences included primary HIV infections (PHIs; <6 months after seroconversion) from the Quebec PHI cohort (1998-2005; n=215) and the provincial genotyping program (2001-2005; n=481). Phylogenetic analysis determined sequence interrelationships among unique PHIs (n=593) and infections from untreated (n=135) and treated (n=660) chronically infected (CI) potential transmitter populations (2001-2005). Clinical features, risk factors, and drug resistance for clustered and nonclustered transmission events were ascertained. RESULTS Viruses from 49.4% (293/593) of PHIs cosegregated into 75 transmission chains with 2-17 transmissions/cluster. Half of the clusters included 2.7+/-0.8 (mean+/-SD) transmissions, whereas the remainder had 8.8+/-3.5 transmissions. Maximum periods for onward transmission in clusters were 15.2+/-9.5 months. Coclustering of untreated and treated CIs with PHIs were infrequent (6.2% and 4.8%, respectively). The ages, viremia, and risk factors were similar for clustered and nonclustered transmission events. Low prevalence of drug resistance in PHI supported amplified transmissions at early stages. CONCLUSIONS Early infection accounts for approximately half of onward transmissions in this urban North American study. Therapy at early stages of disease may prevent onward HIV transmission.

Prevalence, Clearance, and Incidence of Anal Human Papillomavirus Infection in HIV-Infected Men: The HIPVIRG Cohort Study

BACKGROUND Human immunodeficiency virus (HIV)-seropositive men who have sex with men (MSM) are at higher risk of human papillomavirus (HPV) infection. This study was conducted to better understand the natural history of type-specific HPV infection in the anus. METHODS A cohort study was conducted among HIV-seropositive MSM in Montreal to investigate acquisition and loss of anal HPV infection. Participants were followed up every 6 months for 3 years for risk behaviors, HIV-related parameters, and HPV testing. RESULTS HPV DNA was detected in 97.9% of the 247 participants at baseline (median, 5 HPV types). The most common types were HPV-16 (38.2%) and HPV-6 (35.3%). Prevalent HPV-16 infections had the lowest clearance rate (12.2 cleared episodes per 1000 person-months [95% confidence interval {CI}, 8.5-17.7]) and a mean retention time of 36 months (95% CI, 32.7-38.8). The highest incidence rates were found for HPV-16 (10.8 new cases per 1000 person-months [95% CI, 8.0-14.7]), HPV-52 (10.8 new cases per 1000 person-months [95% CI, 8.2-14.1]), and HPV-53 (9.8 new cases per 1000 person-months [95% CI, 7.4-13.0]), with cumulative incidences at 36 months of approximately 30%. CONCLUSIONS Multiple HPV types were common in the anal canals of HIV-seropositive MSM. Incidence and clearance rates were not similar among HPV types. Ongoing surveillance of this cohort will help our understanding of the determinants of HPV persistence and progression to lesions.

Enhanced Detection and Typing of Human Papillomavirus (HPV) DNA in Anogenital Samples with PGMY Primers and the Linear Array HPV Genotyping Test

ABSTRACT The Roche PGMY primer-based research prototype line blot assay (PGMY-LB) is a convenient tool in epidemiological studies for the detection and typing of human papillomavirus (HPV) DNA. This assay has been optimized and is being commercialized as the Linear Array HPV genotyping test (LA-HPV). We assessed the agreement between LA-HPV and PGMY-LB for detection and typing of 37 HPV genotypes in 528 anogenital samples (236 anal, 146 physician-collected cervical, and 146 self-collected cervicovaginal swabs) obtained from human immunodeficiency virus-seropositive individuals (236 men and 146 women). HPV DNA was detected in 433 (82.0%) and 458 (86.7%) samples with PGMY-LB and LA-HPV (P = 0.047), respectively, for an excellent agreement of 93.8% (kappa = 0.76). Of the 17,094 HPV typing results, 16,562 (1,743 positive and 14,819 negative results) were concordant between tests (agreement = 96.9%; kappa = 0.76). The mean agreement between tests for each type was 96.4% ± 2.4% (95% confidence interval [CI], 95.6% to 97.2%; range, 86% to 100%), for an excellent mean kappa value of 0.85 ± 0.10 (95% CI, 0.82 to 0.87). However, detection rates for most HPV types were greater with LA-HPV. The mean number of types per sample detected by LA-HPV (4.2 ± 3.4; 95% CI, 3.9 to 4.5; median, 3.0) was greater than that for PGMY-LB (3.4 ± 3.0; 95% CI, 3.1 to 3.6; median, 2.0) (P < 0.001). The number of types detected in excess by LA-HPV in anal samples correlated with the number of types per sample (r = 0.49 ± 0.06; P = 0.001) but not with patient age (r = 0.03 ± 0.06; P = 0.57), CD4 cell counts (r = 0.06 ± 0.06; P = 0.13), or the grade of anal disease (r = −0.11 ± 0.06; P = 0.07). LA-HPV compared favorably with PGMY-LB but yielded higher detection rates for newer and well-known HPV types.

HAART and Progression to High-Grade Anal Intraepithelial Neoplasia in Men Who Have Sex with Men and Are Infected with HIV

BACKGROUND Human immunodeficiency virus (HIV)-seropositive men who have sex with men (MSM) are at risk for anal intraepithelial neoplasia (AIN) and cancer. The goal of this study was to identify risk factors associated with high-grade AIN (AIN-2,3) in HIV-positive MSM, including the receipt of highly active antiretroviral therapy (HAART). METHODS A cohort study involving 247 HIV-seropositive MSM receiving HAART or initiating HAART was followed up every 6 months for 3 years with human papillomavirus (HPV) testing and high-resolution anoscopy to identify predictors of AIN-2,3 by Cox regression analysis and period prevalence logistic regression. RESULTS AIN-2,3 was observed during the study in 132 (53%) of 247 participants. The progression rate to AIN-2,3 from a lesser abnormality at baseline was 12.8 cases per 1000 person-months (95% confidence interval [CI], 9.8-16.5 cases per 1000 person-months). The risk of AIN-2,3 increased with age (odds ratio [OR], 3.09 [95% CI, 1.12-8.52] for men 40-49 years of age and 4.78 [95% CI, 1.29-17.73] for men >50 years of age, compared with men <40 years of age) and for men whose CD4+ cell counts were <50 cells/mm(3) before starting HAART (OR, 14.40 [95% CI, 1.45-143.58]). Men who had been receiving their current HAART regimen for >4 years had a marginally significant lower risk of AIN-2,3 after adjustment for HPV (OR, 0.28 [95% CI, 0.07-1.06]) compared with those treated for <4 years. Anal HPV type 16 (HPV16) or type 18 (HPV18) infections (OR, 14.18; [95% CI, 3.51-57.32]) and HPV16 and HPV18 co-infection (OR, 31.03 [ 95% CI, 5.68-169.60]) were strongly associated with progression to AIN-2,3. CONCLUSION HPV16 and HPV18 infections and a low nadir CD4+ cell count increase the risk of AIN-2,3. Receiving the same HAART regimen for >4 years may contribute some benefit against AIN-2,3.

Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV‐1 reservoirs: results from a multicentre randomized clinical study

Conflicting results have been reported regarding the ability of valproic acid (VPA) to reduce the size of HIV reservoirs in patients receiving suppressive highly active antiretroviral therapy (HAART). In a randomized multicentre, cross‐over study, we assessed whether adding VPA to stable HAART could potentially reduce the size of the latent viral reservoir in CD4 T cells of chronically infected patients.

Cohort Profile: The Canadian HIV–Hepatitis C Co-infection Cohort Study

Hepatitis C virus (HCV) has emerged as one of the most vexing health problems facing HIV-infected persons. Due largely to injection drug use (IDU),430% of HIV-infected patients are co-infected with HCV in developed countries with 10 million co-infected worldwide. In 1999, 11 194 Canadians were estimated to be co-infected and this number has likely increased substantially since. HCV infection has also increasingly been reported in HIV-positive men having sex with men (MSM) who have not used injection drugs. Since the advent of highly active antiretroviral therapy (HAART) there have been dramatic reductions in morbidity and mortality from virtually all causes of illness among HIV-infected persons. One of the glaring exceptions to this trend is death from end-stage liver disease (ESLD) with rates increasing 4to 8-fold in the post-HAART era. This excess mortality may be due, in part, to improved overall survival associated with HAART, allowing competing morbidities and mortalities that were once rarely observed. In addition, HCVassociated hepatic fibrosis has been shown to progress more rapidly in the context of HIV infection, likely due to immune dysfunction. Several other factors may be at play, including chronic hepatotoxicity related to antiretrovirals, incomplete immune recovery, heavy alcohol use and problems with access and/or adherence to HAART and HCV treatment in a population with high rates of substance use. The growing burden of chronic HCV infection is expected to result in dramatic increases in the rates of cirrhosis, liver failure, hepatocellular carcinoma, transplant needs and related annual healthcare costs in Canada and worldwide. Understanding the complex interplay between sociodemographic factors, substance use, biology and treatments that may affect outcomes in co-infection is necessary to meet the challenge of providing effective

Resistance to antiretroviral drugs in patients with primary HIV-1 infection

The widespread use of antiretroviral agents (ARVs) and the growing occurrence of HIV strains resistant to these drugs have given rise to serious concerns regarding the transmission of resistant viruses to newly infected persons. Plasma viral RNA from 80 individuals newly infected between 1997 and 1999 was genotyped by automated sequencing to analyze the profile of viruses resistant to nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs) and to protease inhibitors (PIs). The prevalence of mutations that conferred primary resistance to PIs (L10I, D30Y, V82A, L90M) was 15% of the cohort. RT genotypic variants, associated with high-level resistance to ARVs, were observed in 21% of individuals, including NRTI, NNRTI and multidrug (MDR) resistance in 6, 5, and 10% of cases, respectively. The phenotypic susceptibility of viral isolates to ARVs was also assayed and showed transmission of high-level resistance to ZDV, 3TC, and PIs in those individuals with MDR. The transmission of drug-resistant HIV genotypic variants is a serious problem that merits further attention by public health officials, virologists, and clinicians.

HIV-associated Lipodystrophy Syndrome: A Review of Clinical Aspects

Approximately two years after the introduction of highly active antiretroviral therapy for the treatment of HIV infection, body shape changes and metabolic abnormalities were increasingly observed. Initially, these were ascribed to protease inhibitors, but it is now clear that nucleoside reverse transcriptase inhibitors also contribute to lipodystrophy syndrome. The syndrome groups together clinical conditions describing changes in body fat distribution that include lipoatrophy, lipoaccumulation or both. However, there does not appear to be a direct link between lipoatrophy and lipoaccumulation that would support a single mechanism for the redistribution of body fat. Currently, there is no clear definition of lipodystrophy, which explains the difficulty in determining its prevalence and etiology. There are no current guidelines for the treatment of fat distribution abnormalities that occur in the absence of other metabolic complications. The present article reviews the current state of knowledge of the definition, symptoms, risk factors, pathogenesis, diagnosis and treatment of the morphological changes associated with lipodystrophy syndrome.

Factors associated with a decrease in the prevalence of drug resistance in newly HIV-1 infected individuals in Montreal.

Objective: A decrease in the prevalence of drug resistance (DR) has been observed among recently infected (RI) individuals in Montreal. A study of chronically infected (CI) patients, who represent potential HIV-1 transmitters, was carried out in order to ascertain biological factors associated with this trend change. Design and methods: Retrospective analysis of CI patients was performed for the period 1996–2003. Changes in mean viral load and DR prevalence were assessed in CI patients (n = 2328) and compared to those in RI patients (n = 180) living in the same geographic area. Results: A decrease was observed in the prevalence of DR among RI patients, from 13.0% in 1997–2000 to 4.0% in 2001–2003 (P = 0.04). From 1996 to 2000, the mean viral load in the CI patients decreased by 1.34 log10, to remain steady thereafter. The proportion of CI patients who interrupt treatment increased steadily over 1997–2003 from 3.1% to 16.5% (P < 0.0001). Since 1999, when genotyping analysis became available, we have observed a 0.9 log10 decrease in mean viral load among 602 genotyped CI patients harbouring any major mutations. Conclusion: The decrease in transmission of DR documented in Montreal since 2000 coincides with the drop in mean viral load observed in CI patients. Factors that contribute to the decrease in viral load include routine access to genotyping and availability of more potent antiretroviral drugs. Plasma viral load seems to represent the main predictor for the transmission of DR.