Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Infection par le papillomavirus à haut risque chez les femmes VIH-positives: épidémiologie, histoire naturelle et impact des thérapies antirétrovirales combinées

L’infection persistante par les papillomavirus (HPV) dits « à haut risque » induit le cancer du col. Chez les femmes infectées par le VIH, les infections par ces HPV oncogènes et les lésions associées, allant des dysplasies au cancer invasif, sont plus fréquentes, plus sévères et de moins bon pronostic que chez les femmes non porteuses du VIH. Etonnamment, alors qu’il a été clairement établi que l’importance de la pathologie liée à HPV est directement proportionnelle au degré d’immunodépression des patientes porteuses du VIH, il n’a pas pu être démontré qu’un traitement antirétroviral efficace contre le VIH permettant d’améliorer l’immunité, diminue l’infection par ces HPV. Entre janvier 2002 et décembre 2012, nous avons constitué une cohorte prospective de dépistage et de suivi de l’infection cervicale par HPV à haut risque incluant plus de 900 femmes traitées à la consultation du Centre de Référence SIDA de l’hôpital Saint-Pierre. Nos résultats montrent que chez ces femmes pour la plupart d’origine Africaine et traitée avec succès pour le VIH depuis plusieurs années, la prévalence et l’incidence de l’infection par HPV oncogène sont beaucoup plus importantes que dans la population belge générale ou que chez les femmes séropositives vivant dans d’autres pays occidentaux. Grâce à un suivi longitudinal de plusieurs années, nous avons pu démontrer que le risque d’être infectée par un HPV oncogène est significativement réduit sous trithérapie anti-VIH sous réserve d’obtenir une charge virale indétectable à 500 lymphocytes CD4+/µL pendant plus d’un an et demi. Ces résultats ont été confirmés dans l’analyse que nous avons faite sur les nombreuses dysplasies cervicales également retrouvées dans notre cohorte. Enfin, nous avons trouvé que la distribution des génotypes d’HPV de nos patientes est similaire à celle trouvée en Afrique sub-saharienne impliquant que la couverture offerte par les vaccins anti-HPV varie entre moins de 30% pour les vaccins bi- ou quadrivalent actuellement disponibles à 80% pour le vaccin nanovalent en développement. Notre travail met en lumière l’étendue particulièrement importante de l’infection par HPV à haut risque chez les femmes séropositives vivant en Belgique et offre de nouveaux éléments de réflexion afin d’adapter à leurs particularités les recommandations belges et les critères de remboursement à la fois pour le dépistage du cancer cervical et la vaccination anti-HPV./Persistent infection with human papillomavirus (HPV) called “at high risk” induces cervical cancer. In HIV-positive women, infection with these oncogenic HPV and HPV-induced lesions ranging from cervical dysplasia to invasive cancer are more frequent, more severe and have a worst outcome than in HIV-negative women. An intriguing paradox is that, although it has been clearly demonstrated that high risk HPV infection and associated diseases are increased by progressive immune deficiency, the introduction of efficient therapy against HIV leading to improved immunity has not been associated with a decrease in oncogenic HPV infection or HPV-induced lesions.Between January 2002 and December 2012, we have built a prospective cohort to screen and follow-up cervical infection by high risk HPV in more than 900 women treated for HIV in the AIDS Reference centre of Saint-Pierre Hospital. We have shown that among these women mainly from Sub-Saharan African origin and successfully treated for HIV for several years, the prevalence and incidence rate of high risk HPV are much higher than in the general population from Belgium or in HIV-positive women from other western countries. After several years of longitudinal follow up, we have demonstrated that the risk of infection by oncogenic HPV is significantly reduced by efficient therapy against HIV provided that HIV viral load has been sustainly suppressed below 50 cp/ml for more than 3 years or that immunity has been increased more than 500 CD4+T cells/µl for more than 1.5 years. These results have been confirmed in the analysis on cervical dysplasia which is also very prevalent in our cohort. At last, we have found that the HPV genotype distribution in our population is very similar to the one found in Sub-Saharan Africa. We have estimated that the coverage offered by the vaccines against HPV in our cohort is less than 30% for the currently available bi- or quadrivalent vaccine but reaches 80% with the future nanovalent vaccine. Our results highlight many differences in the HPV infection and associated diseases in HIV-positive women compared to HIV-negative women; these differences should be taken into account to adapt to our specific population the current Belgian guidelines or the reimbursement criteria on cervical screening and on vaccines against HPV. Doctorat en Sciences médicalesinfo:eu-repo/semantics/nonPublishe

La vaccination préventive contre HPV

Since 2007, two prophylactic vaccines against Human Papillomavirus (HPV) infection and HPV-induced lesions (both precancerous dysplasia and cancer) have been registered in Belgium. In multicentre randomized trials including more than 64,000 patients, these vaccines were shown to be highly efficient against the occurrence of condyloma and of dysplastic lesion in the cervix, vagina and vulva in females and in the anus in males. These vaccines display an excellent tolerance and safety profile, the most common adverse event being minor and transient side effects at the injection site. The protection given by these vaccines is more important in subjects that have not been in contact with HPV previously ;moreover the title of neutralizing antibodies against HPV are significantly higher in children vaccinated before 15 years-old age compared to young person vaccinated after this age. For these two reasons, it is recommended to vaccinate before the first sexual relationships. Recently, several studies have demonstrated that vaccination by two doses given at 0 and 6 months in children before 15 years-old was equivalent to the three doses scheme that should be given at 0, 1 or 2 and 6 months in subjects aged 15 years or more. In the countries that have achieved a high vaccine coverage among their young female population, the prevalence of HPV infection and the incidence of high grade cervical dysplasia have significantly decreased while condyloma has almost disappeared four years after the implementation of HPV vaccination. In HIV-positive subjects who are particularly susceptible to infection and lesions induced by HPV, vaccination brings levels of antibody comparable to what is found in the general population with similar safety.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Chronic hepatitis B and C virus infection and risk for non-hodgkin lymphoma in HIV-infected patients: A cohort study

Background: Non-Hodgkin lymphoma (NHL) is the most common AIDS-defining condition in the era of antiretroviral therapy (ART). Whether chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection promote NHL in HIV-infected patients is unclear. Objective: To investigate whether chronic HBV and HCV infection are associated with increased incidence of NHL in HIVinfected patients. Design: Cohort study. Setting: 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). Patients: HIV-infected patients with information on HBV surface antigen measurements and detectable HCV RNA, or a positive HCV antibody test result if HCV RNA measurements were not available. Measurements: Time-dependent Cox models to assess risk for NHL in treatment-naive patients and those initiating ART, with inverse probability weighting to control for informative censoring. Results: A total of 52 479 treatment-naive patients (1339 [2.6%] with chronic HBV infection and 7506 [14.3%] with HCV infection) were included, of whom 40 219 (77%) later started ART. The median follow-up was 13 months for treatment-naive patients and 50 months for those receiving ART. A total of 252 treatmentnaive patients and 310 treated patients developed NHL, with incidence rates of 219 and 168 cases per 100 000 person-years, respectively. The hazard ratios for NHL with HBV and HCV infection were 1.33 (95% CI, 0.69 to 2.56) and 0.67 (CI, 0.40 to 1.12), respectively, in treatment-naive patients and 1.74 (CI, 1.08 to 2.82) and 1.73 (CI, 1.21 to 2.46), respectively, in treated patients. Limitation: Many treatment-naive patients later initiated ART, which limited the study of the associations of chronic HBV and HCV infection with NHL in this patient group. Conclusion: In HIV-infected patients receiving ART, chronic coinfection with HBV and HCV is associated with an increased risk for NHL.0SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Comparison of Kaposi Sarcoma risk in human immunodeficiency virus-positive adults across 5 continents: A multiregional multicohort study

Background: We compared Kaposi sarcoma (KS) risk in adults who started antiretroviral therapy (ART) across the Asia-Pacific, South Africa, Europe, Latin, and North America. Methods: We included cohort data of human immunodeficiency virus (HIV)-positive adults who started ART after 1995 within the framework of 2 large collaborations of observational HIV cohorts. We present incidence rates and adjusted hazard ratios (aHRs). Results: We included 208 140 patients from 57 countries. Over a period of 1 066 572 person-years, 2046 KS cases were diagnosed. KS incidence rates per 100 000 person-years were 52 in the Asia-Pacific and ranged between 180 and 280 in the other regions. KS risk was 5 times higher in South African women (aHR, 4.56; 95% confidence intervals [CI], 2.73-7.62) than in their European counterparts, and 2 times higher in South African men (2.21; 1.34-3.63). In Europe, Latin, and North America KS risk was 6 times higher in men who have sex with men (aHR, 5.95; 95% CI, 5.09-6.96) than in women. Comparing patients with current CD4 cell counts ≥700 cells/μL with those whose counts were <50 cells/μL, the KS risk was halved in South Africa (aHR, 0.53; 95% CI, 17-1.63) but reduced by ≥95% in other regions. Conclusions. Despite important ART-related declines in KS incidence, men and women in South Africa and men who have sex with men remain at increased KS risk, likely due to high human herpesvirus 8 coinfection rates. Early ART initiation and maintenance of high CD4 cell counts are essential to further reducing KS incidence worldwide, but additional measures might be needed, especially in Southern Africa.0SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Issue fatale chez un patient coinfecté par le VIH et la malaria

Imported malaria is a pathology mainly due to Plasmodium falciparum. For patients with co- morbidities, such as HIV or believing themselves immune, the risk of malaria is more severe. We present the case of a HIV patient carrier with a cerebral malaria of letal evolution despite a rapid decline in its parasitaemia using Artesunate. This case describes the relationship HIV-malaria, stresses the place of Artesunate, and insist on the importance of preventive measures for malaria acquisition for any person with HIV traveling to endemic areas.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

HPV and HIV coinfection: A complex interaction resulting in epidemiological, clinical and therapeutic implications

HPV and HIV each display interactions favoring the other infection at the cellular level. HPV infection favors HIV acquisition in women and men, and HIV-infected individuals encompass a heavier burden of HPV-induced dysplasia and cancer due to progressive immune suppression. Both infections contribute to a vicious circle that may account for the scale-up of both pandemics in some regions of the world. HAART might be beneficial in reducing HPV infection and associated lesions, but only after several years with optimal control of HIV viremia and an immune reconstitution of great amplitude. Yet, the incidence of cervical and anal cancer has not decreased in the HAART era. In this review, we will look at the viral interactions between HPV and HIV at the cellular and clinical levels. We will analyze the epidemiological link between the two epidemics and try to propose therapeutic and vaccine strategies to act on both pandemics. © 2013 Future Medicine Ltd.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Severe adverse events in patients receiving Rifabutin low dose and Ritonavir baby dose

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Comparison of the efficacy and safety of three PI based regimens in naïve patients: nelfinavir 1250 bid of indinavir/ritonavir 800/100 mg bid versus 400/100 bid

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