Cohorte de patients avec le VIH/SIDA : échecs virologiques et effets de thérapies antirétrovirales sur la fonction rénale et l'hyperbilirubinémie

Le virus de l'immunodéficience humaine (VIH) est à l’origine d’une infection chronique, elle-même responsable du développement du syndrome d'immunodéficience acquise (SIDA), un état de grande vulnérabilité où le corps humain est à la merci d’infections opportunistes pouvant s’avérer fatales. Aujourd’hui, 30 ans après la découverte du virus, même si aucun vaccin n’a réussi à contrôler la pandémie, la situation s’est grandement améliorée. Conséquemment à l’arrivée de traitements antirétroviraux hautement actifs (HAART) à la fin des années 1990, la mortalité associée au VIH/SIDA a diminué et un plus grand nombre de personnes vivent maintenant avec l'infection. La présente thèse avait pour objectif d’aborder trois situations problématiques, en dépit de l’efficacité reconnue des HAART, plus particulièrement la faible charge virale persistante (LLV) et sa relation avec l’échec virologique, ainsi que les effets de certains antirétroviraux (ARV) sur les fonctions rénale et hépatique. Les objectifs précis étaient donc les suivants : 1) étudier le risque d’échec virologique à long terme chez les patients sous HAART dont la charge virale est indétectable comparativement aux patients affichant une LLV persistante; 2) évaluer sur le long terme la perte de fonction rénale associée à la prise de ténofovir (TDF) 3) étudier sur le long terme l'hyperbilirubinémie associée à la prise d’atazanavir (ATV) et ses autres déterminants possibles. Afin d’atteindre les trois objectifs susmentionnés, une cohorte de 2 416 patients atteints du VIH/SIDA, suivis depuis juillet 1977 et résidant à Montréal, a été utilisée. Pour le premier objectif, les résultats obtenus ont montré un risque accru d’échec virologique établi à >1000 copies/ml d’ARN VIH chez tous les patients qui présentaient une LLV persistante de différentes catégories durant aussi peu que 6 mois. En effet, on a observé qu’une LLV de 50-199 copies/ml persistant pendant six mois doublait le risque d’échec virologique (Hazard ratio (HR)=2,22, Intervalle de confiance (CI) 95 %:1,60–3,09). Ces résultats pourraient modifier la façon dont on aborde actuellement la gestion des patients affichant une LLV, et plus particulièrement une LLV de 50-199 copies/ml, pour laquelle aucune recommandation clinique n’a encore été formulée en raison du manque de données. Pour le deuxième objectif, on a observé une augmentation du risque de perte de fonction rénale de l’ordre de 63 % (HR=1,63; 95% CI:1,26–2,10) chez les patients sous TDF comparativement aux patients traités avec d’autres ARV. La perte de fonction rénale directement attribuable à la prise de TDF, indique que cette perte est survenue au cours des premières années de l’exposition du patient au médicament. D’une perspective à long terme, cette perte est considérée comme modérée. Enfin, pour ce qui est du troisième objectif, on a constaté que l’incidence cumulative d’hyperbilirubinémie était très élevée chez les patients sous ATV, mais que cette dernière pouvait régresser lorsque l’on mettait fin au traitement. L’hyperbilirubinémie à long terme observée avec la prise d’ATV n’a été associée à aucun effet néfaste pour la santé. Dans l’ensemble, la présente thèse a permis de mieux comprendre les trois situations problématiques susmentionnées, qui font actuellement l’objet de débats au sein de la communauté scientifique, et d’éclairer sous un jour nouveau la gestion des patients séropositifs sous traitement médicamenteux.Human immonudeficiency virus (HIV) is a virus causing a chronic infection responsible for Acquired Immunodeficiency Syndrome (AIDS), a state of vulnerability of the body where different opportunistic infections will ultimately be fatal. About 30 years after the discovery of the virus, even if no vaccine is available to control the pandemia, situation has changed for the best. With the arrival of highly active anti-retroviral therapy (HAART) in the late 90's, a reduction in HIV/AIDS mortality rate and growing number of persons living with the infection were observed. The overall objective of this thesis was to address three problematic situations, despite recognised HAART efficacy, especially low-level viremia (LLV) and its relationship with virologic failure, and the impacts of certain antiretrovirals (ARV) on kidney and hepatic functions. The specific objectives were: 1) to study the risk of virologic failure in long-term perspective in undetectable patients under HAART in comparison to patients with persistent LLV; 2) to evaluate the long-term loss of kidney function related to tenofovir (TDF) exposure 3) to evaluate long-term hyperbilirubinemia related to atazanavir (ATV) exposure and other possible determinants. In order to address the three specific objectives, a cohort of patients 2416 living with HIV/AIDS followed in Montreal since July 1977 was used. For the first objective, analyses and results shown an increased risk of virological failure defined as >1000 copies/mL of HIV RNA, for all categories of persistent LLV as soon as 6 months of persistent duration. Persistent LLV of 50-199 copies/mL for 6 months doubled the risk of virologic failure (Hazard ratio (HR)=2,22, Confidence interval (CI) 95%: 1,60-3,09). The results shed new light for the management of patients with LLV, especially for LLV of 50-199 copies/mL, for which no clinical recommendation is currently available due to a lack of data. For the second objective, an increased risk of loss of kidney function of 63% (HR=1.63; 95% CI:1.26–2.10) associated to TDF exposure in comparison to patients taking other ARV was observed. The cumulative eGFR loss directly attribuable to TDF also shown that this loss occured during the first years of exposure. This loss was mild in a long-term perspective. For the third objective, it has been shown that the cumulative incidence of hyperbilirubinemia in ATV users was very high and that regression was possible if ATV exposure was ended. Long-term hyperbilirubinemia related to ATV use was not associated with adverse health outcome. Overall, this thesis allowed a better understanding of these three problematics currently debated in scientific literature and shed new lights on management of HIV positive patients under therapy

Detection of Fusobacterium nucleatum in feces and colorectal mucosa as a risk factor for colorectal cancer : a systematic review and meta-analysis

Background: Colorectal cancer (CRC) is a major cause of cancer deaths worldwide. Accumulating evidence suggests a potentially important role of colorectal infection with Fusobacterium nucleatum (F. nucleatum) in colorectal carcinogenesis. We conducted a systematic review, including both a qualitative synthesis and a metaanalysis, to synthesize the evidence from the epidemiological literature on the association between F. nucleatum detection in the colon/rectum and CRC. Methods: A systematic literature search of Ovid MEDLINE(R), Embase, Web of Science Core Collection, EBM Reviews—Cochrane Database of Systematic Reviews, and CINAHL Plus with Full Text was conducted using earliest inclusive dates up to 4 October 2020. Eligible studies were original, comparative observational studies that reported results on colorectal F. nucleatum detection and CRC. Two independent reviewers extracted the relevant information. Odds ratio (OR) estimates were pooled across studies using the random effects model. NewcastleOttawa scale was used to critically appraise study quality. Results: Twenty-four studies were included in the systematic review, of which 12 were included in the metaanalysis. Studies investigated F. nucleatum in feces, colorectal tissue samples, or both. In most studies included in the systematic review, the load of F. nucleatum was higher, on average, in specimens from CRC patients than in those from CRC-free controls. Meta-analysis showed a positive association between F. nucleatum detection in colorectal specimens and CRC (OR = 8.3; 95% confidence interval (95% CI) 5.2 to 13.0). Conclusions: The results of this systematic review suggest that F. nucleatum in the colon/rectum is associated with CRC

Human papillomavirus concordance between parents and their newborn offspring : Results from the Finnish Family HPV study

BACKGROUND: The knowledge on vertical human papillomavirus (HPV) transmission is limited. We aimed to determine whether HPV transmission from parents to their offspring occur before or during birth. METHODS: Altogether, 321 mothers, 134 fathers and their 321 newborn offspring from the Finnish Family HPV study cohort were included. Parents' genital and oral brush samples and semen samples were collected for HPV testing at baseline (36 weeks of pregnancy). Oral, genital and umbilical samples from the newborn and placenta samples were collected for HPV testing immediately after delivery. HPV risk for the newborn was calculated from mother's and father's HPV status by using logistic regression analyses. RESULTS: Concordances between mothers' and their newborns' HPV genotype at any site were statistically significant with HPV6, HPV16, HPV18, HPV31 and HPV56; Odds Ratios (OR) ranged from OR 3.41 (95% CI: 1.80-6.48) for HPV16 to OR 634 (95% CI: 28.5-14087) for HPV31. Father-newborn HPV concordances were statistically significant with HPV6 and HPV31; OR 4.89 (95% CI: 1.09-21.9) and OR 65.0 (95% CI: 2.92-1448), respectively.ConclusionsThe genotype-specific HPV concordance between parents and their newborn is suggestive for vertical HPV transmission. However, transmission from the father to the newborn remains more uncertain.Peer reviewe

Virologic failure following persistent low-level viremia in a cohort of HIV-positive patients: results from 12 years of observation,”

Background. The current goal of antiretroviral therapy (ART) is to maintain a suppressed human immunodeficiency virus (HIV) viral load below limits of assay detection. When viral loads remain in low-level viremia (LLV), especially between 50 and 200 copies/mL, the best management and clinical consequences remain unknown. Our objective was to study the long-term impact of persistent LLV on the subsequent risk of virologic failure in a cohort of people living with HIV in Montreal, Canada. Methods. We compared the cumulative incidence of subsequent virologic failure (defined as an HIV RNA viral load of >1000 copies/mL) in patients receiving ART for at least 12 months by following 4 persistence categories (<50, 50-199, 200-499, and 500-999 copies/mL) for 6, 9, or 12 months, using Kaplan-Meier analysis. The association between subsequent virologic failure and persistence status were estimated using a Cox proportional hazards model. Results. The cumulative incidence of virologic failure 1 year after having maintained a LLV for 6 months was 22.7% (95% confidence interval [CI], 14.9-33.6) for 50-199 copies/mL, 24.2% (95% CI, 14.5-38.6) for 200-499 copies/mL, and 58.9% (95% CI, 43.1-75.2) for 500-999 copies/mL, compared with 6.6% (95% CI, 5.3-8.2) for an undetectable HIV RNA viral load. Even after adjustment for potential confounders, a persistent LLV of 50-199 copies/ mL for 6 months doubled the risk of virologic failure (hazard ratio, 2.22; 95% CI, 1.60-3.09), compared with undetectable viral loads for the same duration. Similar results have been found for persistent LLV of 9 or 12 months. Conclusions. In this cohort, all categories of persistent LLV between 50 and 999 copies/mL were associated with an increased risk of virologic failure. The results shed new light for the management of patients with LLV, especially with regard to LLV of 50-199 copies/mL

Sex and gender considerations in transplantation research: protocol for a scoping review

Abstract Background Despite the growing appreciation of the importance of sex and gender considerations in transplantation research, there is currently no framework or good practice guidelines for the appropriate handling of sex and gender issues in human allotransplantation research. Methods We will conduct a scoping review to synthesize the evidence on how matters of sex and gender have been handled in human allotransplantation research. We will survey the literature discussing sex and gender in relation to transplantation, including adult and pediatric patients, hematopoietic and solid organ transplant recipients as well as organ donors. We will search MEDLINE and Embase for literature discussing sex and gender in relation to transplantation. Two reviewers will independently evaluate the eligibility of all identified titles and abstracts for inclusion in the full text review, as well as data extraction. Descriptive data and information on how sex and gender have been considered in human transplantation research will be reported. Discussion This scoping review will be an important stepping stone towards the development of good practice guidelines on study design and analysis considerations when handling sex and gender issues in human transplantation research. This scoping review can also help identify methodological issues that restrict the translation of transplantation research findings into clinical practice related to underestimation of sex/gender differences. This review will ultimately identify major gaps, inform donor-recipient selection, guide personalized interventions, and prioritize research recommendations in human transplantation research

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Increased risk of oropharyngeal cancers mediated by oral human papillomavirus infection: Results from a Canadian study

International audienceBACKGROUND: This study aimed to estimate the extent to which oral sex behavior is associated with an increased risk of oropharyngeal cancers (OPCs), and how much of the association is mediated by oral human papillomavirus (HPV) infection.METHODS: We used data from a hospital-based case-control study conducted in Montreal, Canada. Information on oral sex behaviors was collected. Oral rinse and oral brush specimens were analyzed for HPV positivity and genotyping. Logistic regression estimated the odds ratios (OR) and 95% confidence intervals (CI) for the association between oral sex behaviors and OPC.RESULTS: Onset of oral sex practice at age 16 years or younger had an increased risk of OPCs relative to those with onset after age 30 years (OR = 2.98; 95% CI 1.37-6.47). This association decreased (OR = 1.09; 95% CI 0.25-4.71) when restricted to those positive for HPV.CONCLUSIONS: Our results suggest that the association between oral sex and OPC seems mediated by oral HPV infection

Human papillomavirus genotypes and risk of head and neck cancers: Results from the HeNCe Life case-control study

International audienceOBJECTIVE:Human papillomaviruses (HPV) are changing dramatically the epidemiologic landscape of head and neck cancers (HNCs). Their role in the aetiology of these cancers varies widely among HNCs subsites, sex and geographical regions worldwide. We describe HPV prevalence and its association with HNCs risk overall and by anatomical subsite in a sample of Canadians.MATERIALS AND METHODS:The HeNCe Life study recruited 460 incident HNCs cases and 458 controls frequency-matched by age and sex from four Montreal hospitals in 2005-2013. We tested oral rinse and oral brush specimens for mucosal HPV genotypes. HPV positivity was categorized hierarchically as either negative, exclusively non-α-9 species types, α-9 types other than HPV16, and HPV16. We estimated odds ratios (OR) and 95% confidence intervals (CI) for the associations between HPV and HNCs using unconditional logistic regression, controlling for confounders.RESULTS:The prevalence of HPV infection among controls and cases was 14.5% and 41.2% in oral rinse and 3.1% and 24.4% in oral brush samples, respectively. HPV16 was the predominant genotype with an oral rinse and oral brush prevalence of 26.3% and 16.2% among cases and 2.4% and 0.2% among controls, respectively. HPV infection was associated with an increased risk of HNCs overall (OR=4.18; 95% CI, 2.94-5.95) and oropharyngeal cancer only (OR=10.3; 95% CI, 6.8-15.7). HNCs and oropharyngeal cancer were strongly associated with HPV16 (OR=18.1; 95% CI, 9.1-35.8, and OR=47.2; 95% CI, 23.1-96.6, respectively).CONCLUSION:HPV infection, particularly HPV16, was associated with an increased HNCs risk, most strongly for oropharyngeal cancers