Hugues Charest

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.

Association between the 2008-09 seasonal influenza vaccine and pandemic H1N1 illness during Spring-Summer 2009: four observational studies from Canada.

BACKGROUND In late spring 2009, concern was raised in Canada that prior vaccination with the 2008-09 trivalent inactivated influenza vaccine (TIV) was associated with increased risk of pandemic influenza A (H1N1) (pH1N1) illness. Several epidemiologic investigations were conducted through the summer to assess this putative association. METHODS AND FINDINGS STUDIES INCLUDED (1) test-negative case-control design based on Canadas sentinel vaccine effectiveness monitoring system in British Columbia, Alberta, Ontario, and Quebec; (2) conventional case-control design using population controls in Quebec; (3) test-negative case-control design in Ontario; and (4) prospective household transmission (cohort) study in Quebec. Logistic regression was used to estimate odds ratios for TIV effect on community- or hospital-based laboratory-confirmed seasonal or pH1N1 influenza cases compared to controls with restriction, stratification, and adjustment for covariates including combinations of age, sex, comorbidity, timeliness of medical visit, prior physician visits, and/or health care worker (HCW) status. For the prospective study risk ratios were computed. Based on the sentinel study of 672 cases and 857 controls, 2008-09 TIV was associated with statistically significant protection against seasonal influenza (odds ratio 0.44, 95% CI 0.33-0.59). In contrast, estimates from the sentinel and three other observational studies, involving a total of 1,226 laboratory-confirmed pH1N1 cases and 1,505 controls, indicated that prior receipt of 2008-09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring-summer 2009, with estimated risk or odds ratios ranging from 1.4 to 2.5. Risk of pH1N1 hospitalization was not further increased among vaccinated people when comparing hospitalized to community cases. CONCLUSIONS Prior receipt of 2008-09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring-summer 2009 in Canada. The occurrence of bias (selection, information) or confounding cannot be ruled out. Further experimental and epidemiological assessment is warranted. Possible biological mechanisms and immunoepidemiologic implications are considered.

Low 2012–13 Influenza Vaccine Effectiveness Associated with Mutation in the Egg-Adapted H3N2 Vaccine Strain Not Antigenic Drift in Circulating Viruses

Background Influenza vaccine effectiveness (VE) is generally interpreted in the context of vaccine match/mismatch to circulating strains with evolutionary drift in the latter invoked to explain reduced protection. During the 2012–13 season, however, detailed genotypic and phenotypic characterization shows that low VE was instead related to mutations in the egg-adapted H3N2 vaccine strain rather than antigenic drift in circulating viruses. Methods/Findings Component-specific VE against medically-attended, PCR-confirmed influenza was estimated in Canada by test-negative case-control design. Influenza A viruses were characterized genotypically by amino acid (AA) sequencing of established haemagglutinin (HA) antigenic sites and phenotypically through haemagglutination inhibition (HI) assay. H3N2 viruses were characterized in relation to the WHO-recommended, cell-passaged vaccine prototype (A/Victoria/361/2011) as well as the egg-adapted strain as per actually used in vaccine production. Among the total of 1501 participants, influenza virus was detected in 652 (43%). Nearly two-thirds of viruses typed/subtyped were A(H3N2) (394/626; 63%); the remainder were A(H1N1)pdm09 (79/626; 13%), B/Yamagata (98/626; 16%) or B/Victoria (54/626; 9%). Suboptimal VE of 50% (95%CI: 33–63%) overall was driven by predominant H3N2 activity for which VE was 41% (95%CI: 17–59%). All H3N2 field isolates were HI-characterized as well-matched to the WHO-recommended A/Victoria/361/2011 prototype whereas all but one were antigenically distinct from the egg-adapted strain as per actually used in vaccine production. The egg-adapted strain was itself antigenically distinct from the WHO-recommended prototype, and bore three AA mutations at antigenic sites B [H156Q, G186V] and D [S219Y]. Conversely, circulating viruses were identical to the WHO-recommended prototype at these positions with other genetic variation that did not affect antigenicity. VE was 59% (95%CI:16–80%) against A(H1N1)pdm09, 67% (95%CI: 30–85%) against B/Yamagata (vaccine-lineage) and 75% (95%CI: 29–91%) against B/Victoria (non-vaccine-lineage) viruses. Conclusions These findings underscore the need to monitor vaccine viruses as well as circulating strains to explain vaccine performance. Evolutionary drift in circulating viruses cannot be regulated, but influential mutations introduced as part of egg-based vaccine production may be amenable to improvements.

Component-Specific Effectiveness of Trivalent Influenza Vaccine as Monitored through a Sentinel Surveillance Network in Canada, 2006–2007

BACKGROUND Trivalent inactivated influenza vaccine (TIV) is reformulated annually to contain representative strains of 2 influenza A subtypes (H1N1 and H3N2) and 1 B lineage (Yamagata or Victoria). We describe a sentinel surveillance approach to link influenza variant detection with component-specific vaccine effectiveness (VE) estimation. METHODS The 2006-2007 TIV included A/NewCaledonia/20/1999(H1N1)-like, A/Wisconsin/67/2005(H3N2)-like, and B/Malaysia/2506/2004(Victoria)-like components. Included participants were individuals >or=9 years of age who presented within 1 week after influenza like illness onset to a sentinel physician between November 2006 and April 2007. Influenza was identified by real-time reverse-transcriptase polymerase chain reaction and/or culture. Isolates were characterized by hemagglutination inhibition assay (HI) and HA1 gene sequence. VE was estimated as 1-[odds ratio for influenza in vaccinated versus nonvaccinated persons]. RESULTS A total of 841 participants contributed: 69 (8%) were >or=65 years of age; 166 (20%) received the 2006-2007 TIV. Influenza was detected in 337 subjects (40%), distributed as follows: A/H3N2, 242 (72%); A/H1N1, 55 (16%); and B, 36 (11%). All but 1 of the A/H1N1 isolates were well matched, half of A/H3N2 isolates were strain mismatched, and all B isolates were lineage-level mismatched to vaccine. Age-adjusted estimated VE for A/H1N1, A/H3N2, and B components was 92% (95% CI, 40%-91%), 41% (95% CI, 6%-63%), and 19% (95% CI, -112% to 69%), respectively, with an overall VE estimate of 47% (95% CI, 18%-65%). Restriction of the analysis to include only working-age adults resulted in lower VE estimates with wide confidence intervals but similar component-specific trends. CONCLUSIONS Sentinel surveillance provides a broad platform to link new variant detection and the composite of circulating viruses to annual monitoring of component-specific VE.

Transmission networks of drug resistance acquired in primary/early stage HIV infection

Objectives:Population-based sequencing of primary/recent HIV infections (PHIs) can provide a framework for understanding transmission dynamics of local epidemics. In Quebec, half of PHIs represent clustered transmission events. This study ascertained the cumulative implications of clustering on onward transmission of drug resistance. Methods:HIV-1 pol sequence datasets were available for all genotyped PHI (<6 months postseroconversion; n = 848 subtype B infections, 1997–2007). Phylogenetic analysis established clustered transmission events, based on maximum likelihood topologies having high bootstrap values (>98%) and short genetic distances. The distributions of resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors and protease inhibitors in unique and clustered transmissions were ascertained. Results:Episodic clustering was observed in half of recent/early stage infections from 1997–2008. Overall, 29 and 28% of new infections segregated into small (<5 PHI/cluster, n = 242/848) and large transmission chains (≥5 PHI/cluster, n = 239/848), averaging 2.8 ± 0.1 and 10.3 ± 1.0 PHI/cluster, respectively. The transmission of nucleoside analogue mutations and 215 resistant variants (T215C/D/I/F/N/S/Y) declined with clustering (7.9 vs. 3.4 vs. 1.2 and 5.8 vs. 1.7 vs. 1.1% for unique, small, and large clustered transmissions, respectively). In contrast, clustering was associated with the increased transmission of viruses harbouring resistance to nonnucleoside reverse transcriptase inhibitors (6.6 vs. 6.0 vs. 15.5%, respectively). Conclusion:Clustering in early/PHI stage infection differentially affects transmission of drug resistance to different drug classes. Public health, prevention and diagnostic strategies, targeting PHI, afford a unique opportunity to curb the spread of transmitted drug resistance.

Effectiveness of AS03 adjuvanted pandemic H1N1 vaccine: case-control evaluation based on sentinel surveillance system in Canada, autumn 2009

Objective To assess the effectiveness of the pandemic influenza A/H1N1 vaccine used in Canada during autumn 2009. Design Test negative incident case-control study based on sentinel physician surveillance system. Setting Community based clinics contributing to sentinel networks in British Columbia, Alberta, Ontario, and Quebec, Canada. Participants 552 patients who presented to a sentinel site within seven days of onset of influenza-like illness during the primary analysis period between 8 November and 5 December 2009; participants were mostly (>80%) children and adults under 50 years old. Interventions Monovalent AS03 adjuvanted pandemic influenza A/H1N1 vaccine as the predominant formulation (>95%) distributed in Canada. Main outcome measures Vaccine effectiveness calculated as 1−(odds ratio for influenza in vaccinated (received pandemic H1N1 vaccine at least two weeks before onset of influenza-like illness) versus unvaccinated participants), with adjustment for age, comorbidity, province, timeliness of specimen collection, and week of illness onset. Sensitivity analyses explored the influence of varying analysis periods between 1 November and 31 December, receipt of trivalent seasonal influenza vaccine, and restriction to participants without comorbidity. Results During the primary analysis period, pandemic H1N1 was detected by reverse transcription polymerase chain reaction in 209/552 (38%) participants; rates were highest in children and young adults (40%) and lowest in people aged 65 or over (9%). Among the 209 cases, 35 (17%) reported comorbidity compared with 80/343 (23%) controls. Two (1%) cases had received pandemic H1N1 vaccine at least two weeks before the onset of illness, compared with 58/343 (17%) controls, all single dose. Adjusted vaccine effectiveness overall was 93% (95% confidence interval 69% to 98%). High estimates of vaccine protection—generally at least 90%—were maintained across most sensitivity analyses. Conclusions Although limited by a small number of vaccine failures, this study suggests that the monovalent AS03 adjuvanted vaccine used in Canada during autumn 2009 was highly effective in preventing medically attended, laboratory confirmed pandemic H1N1 illness, with reference in particular to a single dose in children and young adults.

Household Transmission of the 2009 Pandemic A/H1N1 Influenza Virus: Elevated Laboratory-Confirmed Secondary Attack Rates and Evidence of Asymptomatic Infections

BACKGROUND Characterizing household transmission of the 2009 pandemic A/H1N1 influenza virus (pH1N1) is critical for the design of effective public health measures to mitigate spread. Our objectives were to estimate the secondary attack rates (SARs), the proportion of asymptomatic infections, and risk factors for pH1N1 transmission within households on the basis of active clinical follow-up and laboratory-confirmed outcomes. METHODS We conducted a prospective observational study during the period May-July 2009 (ie, during the first wave of the pH1N1 pandemic) in Quebec City, Canada. We assessed pH1N1 transmission in 42 households (including 43 primary case patients and 119 contacts). Clinical data were prospectively collected during serial household visits. Secondary case patients were identified by clinical criteria and laboratory diagnostic tests, including serological and molecular methods. RESULTS We identified 53 laboratory-confirmed secondary case patients with pH1N1 virus infection, for an SAR of 45% (95% confidence interval [CI], 35.6%-53.5%). Thirty-four (81%) of the households had ≥1 confirmed secondary case patient. The mean serial interval between onset of primary and confirmed secondary cases was 3.9 days (median interval, 3 days). Influenza-like illness (fever and cough or sore throat) developed in 29% (95% CI, 20.5%-36.7%) of household contacts. Five (9.4%) of secondary case patients were asymptomatic. Young children (<7 years of age) were at highest risk of developing laboratory-confirmed influenza-like illness. Primary case patients with both diarrhea and vomiting were the most likely to transmit pH1N1. CONCLUSION Household transmission of pH1N1 may be substantially greater than previously estimated, especially in association with clinical presentations that include gastrointestinal complaints. Approximately 10% of pH1N1 infections acquired in the household may be asymptomatic.

A Sentinel Platform to Evaluate Influenza Vaccine Effectiveness and New Variant Circulation, Canada 2010–2011 Season

BACKGROUND During the 2010-2011 winter, a large number of outbreaks due to influenza A/H3N2 at long-term care facilities, including higher-than-expected attack rates among vaccinated staff, were reported in some regions of Canada. Interim analysis from the community-based sentinel surveillance system showed circulating H3N2 variants and suboptimal vaccine effectiveness (VE), assessed here for the entire seasons data set. METHODS Nasal/nasopharyngeal swabs and epidemiologic details were collected from patients presenting to sentinel sites within 7 days of onset of influenza-like illness. Cases tested positive for influenza by real-time reverse-transcription polymerase chain reaction; controls tested negative. Odds ratios for medically attended, laboratory-confirmed influenza in vaccinated vs nonvaccinated participants were used to derive adjusted VE. Viruses were characterized by hemagglutination inhibition (HI), and the hemagglutinin genes of a subset were sequenced to explore vaccine relatedness. RESULTS Final 2010-2011 VE analysis included 1718 participants (half aged 20-49 years), 93 with A(H1N1)pdm09, 408 with A/H3N2, and 199 with influenza B. Among adults aged 20-49 years, adjusted VE was 65% (95% confidence interval [CI], 8%-87%) for A(H1N1)pdm09 and 66% (95% CI, 10%-87%) for influenza B. Vaccine effectiveness was substantially lower for A/H3N2, at 39% (95% CI, 0%-63%). Phylogenetic analysis identified 2 circulating H3N2 variant clades, A/HongKong/2121/2010 (87%) and A/Victoria/208/2009 (11%), bearing multiple amino acid substitutions at antigenic sites (12 and 8, respectively) compared with the H3N2 vaccine component used in Canada (A/Victoria/210/2009[NYMC X-187]). However, HI characterized all H3N2 isolates as well matched to the vaccine. CONCLUSIONS Public health observations of increased facility H3N2 outbreaks were consistent with the sentinel networks detection of genetic variants and suboptimal VE but not with conventional HI characterization. We highlight the utility of a multicomponent sentinel surveillance platform that incorporates genotypic, phenotypic, and epidemiologic indicators into the assessment of influenza virus, new variant circulation, vaccine relatedness, and VE.

Transmission Clustering Drives the Onward Spread of the HIV Epidemic Among Men Who Have Sex With Men in Quebec

Phylodynamic analysis and epidemiologic data identified 3 patterns of spread of primary human immunodeficiency virus type 1 infection (PHI) among men who have sex with men (2001-2009): 420 unique PHIs, 102 small clusters (2-4 PHIs per cluster, n = 280), and 46 large clusters (5-31 PHIs per cluster, n = 450). Large clusters disproportionately increased from 25.2% of PHIs in 2005 to 39.1% in 2009 (χ(2) = 33.9, P < .001). Scalar expansion of large clusters over 11 months (interquartile range, 3.5-25.5 months) correlated with cluster membership size (r(2) = 0.174, F = 4.424, P = .047). PHI cohort data revealed variations in social networks and risk behaviors among the 3 groups, suggesting the need for tailored prevention measures.

Interim estimates of 2014/15 vaccine effectiveness against influenza A(H3N2) from Canada's Sentinel Physician Surveillance Network, January 2015.

The 2014/15 influenza season to date in Canada has been characterised by predominant influenza A(H3N2) activity. Canadas Sentinel Physician Surveillance Network (SPSN) assessed interim vaccine effectiveness (VE) against medically attended, laboratory-confirmed influenza A(H3N2) infection in January 2015 using a test-negative case-control design. Of 861 participants, 410 (48%) were test-positive cases (35% vaccinated) and 451 (52%) were test-negative controls (33% vaccinated). Among test-positive cases, the majority (391; 95%) were diagnosed with influenza A, and of those with available subtype information, almost all influenza A viruses (379/381; 99%) were A(H3N2). Among 226 (60%) A(H3N2) viruses that were sequenced, 205 (91%) clustered with phylogenetic clade 3C.2a, considered genetically and antigenically distinct from the 2014/15 A/Texas/50/2012(H3N2)-like clade 3C.1 vaccine reference strain, and typically bearing 10 to 11 amino acid differences from the vaccine at key antigenic sites of the haemagglutinin protein. Consistent with substantial vaccine mismatch, little or no vaccine protection was observed overall, with adjusted VE against medically attended influenza A(H3N2) infection of ?8% (95% CI: ?50 to 23%). Given these findings, other adjunct protective measures should be considered to minimise morbidity and mortality, particularly among high-risk individuals. Virus and/or host factors influencing this reduced vaccine protection warrant further in-depth investigation. .