A community-based healthcare package combining testing and prevention tools, including pre-exposure prophylaxis (PrEP), immediate HIV treatment, management of hepatitis B virus, and sexual and reproductive health (SRH), targeting female sex workers (FSWs) in Cote d'Ivoire: the ANRS 12381 PRINCESSE project

BACKGROUND: Pre-exposure prophylaxis (PrEP) is recommended by the WHO for HIV prevention among female sex workers (FSWs). A study conducted in 2016-2017 in Côte d'Ivoire showed that if PrEP is acceptable, FSWs also have many uncovered sexual health needs. Based on this evidence, the ANRS 12381 PRINCESSE project was developed in collaboration with a community-based organization. The main objective is to develop, document, and analyze a comprehensive sexual and reproductive healthcare package among FSWs in Côte d'Ivoire. METHODS: PRINCESSE is an open, single-arm interventional cohort of 500 FSWs in San Pedro (Côte d'Ivoire) and its surroundings. Recruitment started on November 26th, 2019 and is ongoing; the cohort is planned to last at least 30 months. The healthcare package (including HIV, hepatitis B, and sexually transmitted infection management, pregnancy screening, and contraception) is available both at mobile clinics organized for a quarterly follow-up (10 intervention sites, each site being visited every two weeks) and at a fixed clinic. Four waves of data collection were implemented: (i) clinical and safety data; (ii) socio-behavioral questionnaires; (iii) biological data; and (iv) in-depth interviews with female participants. Four additional waves of data collection are scheduled outside the cohort itself: (i) the medical and activity records of Aprosam for the PRINCESSE participants; (ii) the medical records of HIV+ FSW patients not participating in the PRINCESSE cohort, and routinely examined by Aprosam; (iii) in-depth interviews with key informants in the FSW community; and (iv) in-depth interviews with PRINCESSE follow-up actors. DISCUSSION: The PRINCESSE project is one of the first interventions offering HIV oral PrEP as part of a more global sexual healthcare package targeting both HIV- and HIV+ women. Second, STIs and viral hepatitis B care were offered to all participants, regardless of their willingness to use PrEP. Another innovation is the implementation of mobile clinics for chronic/quarterly care. In terms of research, PRINCESSE is a comprehensive, interdisciplinary project combining clinical, biological, epidemiological, and social specific objectives and outcomes to document the operational challenges of a multidisease program in real-life conditions. TRIAL REGISTRATION: The PRINCESSE project was registered on the Clinicaltrial.gov website ( NCT03985085 ) on June 13, 2019

Kaposi’s Sarcoma-Associated Herpesvirus, the Etiological Agent of All Epidemiological Forms of Kaposi’s Sarcoma

Kaposi’s sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is an oncogenic virus belonging to the Herpesviridae family. The viral particle is composed of a double-stranded DNA harboring 90 open reading frames, incorporated in an icosahedral capsid and enveloped. The viral cycle is divided in the following two states: a short lytic phase, and a latency phase that leads to a persistent infection in target cells and the expression of a small number of genes, including LANA-1, v-FLIP and v-cyclin. The seroprevalence and risk factors of infection differ around the world, and saliva seems to play a major role in viral transmission. KSHV is found in all epidemiological forms of Kaposi’s sarcoma including classic, endemic, iatrogenic, epidemic and non-epidemic forms. In a Kaposi’s sarcoma lesion, KSHV is mainly in a latent state; however, a small proportion of viral particles (<5%) are in a replicative state and are reported to be potentially involved in the proliferation of neighboring cells, suggesting they have crucial roles in the process of tumorigenesis. KSHV encodes oncogenic proteins (LANA-1, v-FLIP, v-cyclin, v-GPCR, v-IL6, v-CCL, v-MIP, v-IRF, etc.) that can modulate cellular pathways in order to induce the characteristics found in all cancer, including the inhibition of apoptosis, cells’ proliferation stimulation, angiogenesis, inflammation and immune escape, and, therefore, are involved in the development of Kaposi’s sarcoma

Molecular and clinical determinants of human herpesvirus 8 infection : factors involved in the transmission of HHV-8 and the development of the associated diseases

L'herpèsvirus humain 8 (HHV-8) est impliqué dans toutes les formes de maladie de Kaposi (MK) mais également dans certaines formes de maladie de Castleman multicentrique (MCM) et dans le lymphome primitif des séreuses (LPS). Ce travail avait pour objectif d’étudier les déterminants cliniques et virologiques impliqués dans l’infection HHV-8 et les maladies qui lui sont liées. Ainsi dans l’étude 1, la charge virale HHV-8 associée à la MK était inférieure à celles retrouvées dans les hémopathies, probablement dû à la physiopathologie de chaque maladie, mais d’autres facteurs pourraient également intervenir. En effet dans l’étude 2, le sous-type HHV-8 influençait la charge virale et la sévérité du tableau clinique dans la MK. De plus, nous avons identifié un nouveau variant systématiquement associé à des formes cliniques graves, renforçant le postulat de déterminants virologiques intervenant dans la physiopathologie des différentes maladies. Malgré l’ère des antirétroviraux, l’immunité jouerait également toujours un rôle important puisque dans l’étude 1, le taux de CD4 était faible et inversement corrélé à la charge virale HHV-8 dans la MK et la MCM alors que dans l’étude 3, les MK épidémiques avec une réponse immunologique et virologique soutenue pour l’infection VIH, étaient associées à un ratio CD4/CD8 inférieur à 1. Enfin dans l’étude 4, l‘analyse in vitro de l’effet du poppers sur le HHV-8 a montré qu’il stimulait la réplication virale. Ce résultat suggère que son utilisation in vivo pourrait être un facteur environnemental favorisant la transmission HHV-8 mais également le développement de MK chez des patients avec une immunité apparente normale ou restaurée.The human herpesvirus 8 is an oncogenic virus involved in the development of all forms of Kaposi’s sarcoma (KS), but also in certain forms of multicentric Castleman disease (MCD) and in primary effusion lymphoma (PEL). The aim of this work was to study the clinical and virological determinants in HHV-8 infection and associated with its three main diseases. Thus, in the study 1, the HHV-8 DNA viral load associated with KS was lower compared with that found in hemopathies, probably due to the pathophysiology of each disease, but other factors could also be involved. Indeed, in the study 2, the HHV-8 subtype influenced the viral load and the severity of the clinical presentation of KS. In addition, we have identified a new variant associated with severe clinical forms, reinforcing the postulate of virological determinants involved in the pathophysiology of the different diseases. Despite the era of antiretrovirals, immunity would still play an important role because in the study 1, the CD4 count was low and inversely correlated with the HHV-8 viral load in KS and MCD whereas in study 3, epidemic KSs with a sustained immunological and virological response for HIV infection were associated with a CD4 / CD8 ratio of less than 1. Finally, in the study 4, in vitro analysis of the effect of poppers on BC-3 cells chronically infected by HHV-8 has been shown to stimulate viral replication. This result suggests that poppers used in vivo could be an environmental factor favoring the transmission of HHV-8 but also the development of MK in patients with apparent normal or restored immunity

Kaposi’s Sarcoma-Associated Herpesvirus, the Etiological Agent of All Epidemiological Forms of Kaposi’s Sarcoma

International audienceSimple SummaryKaposi’s sarcoma-associated herpesvirus (KSHV) is one of the seven oncogenic viruses currently recognized by the International Agency for Research on Cancer. Its presence for Kaposi’s sarcoma development is essential and knowledge on the oncogenic process has increased since its discovery in 1994. However, some uncertainties remain to be clarified, in particular on the exact routes of transmission and disparities in KSHV seroprevalence and the prevalence of Kaposi’s sarcoma worldwide. Here, we summarized the current data on the KSHV viral particle’s structure, its genome, the replication, its seroprevalence, the viral diversity and the lytic and latent oncogenesis proteins involved in Kaposi’s sarcoma. Lastly, we reported the environmental, immunological and viral factors possibly associated with KSHV transmission that could also play a role in the development of Kaposi’s sarcoma.AbstractKaposi’s sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is an oncogenic virus belonging to the Herpesviridae family. The viral particle is composed of a double-stranded DNA harboring 90 open reading frames, incorporated in an icosahedral capsid and enveloped. The viral cycle is divided in the following two states: a short lytic phase, and a latency phase that leads to a persistent infection in target cells and the expression of a small number of genes, including LANA-1, v-FLIP and v-cyclin. The seroprevalence and risk factors of infection differ around the world, and saliva seems to play a major role in viral transmission. KSHV is found in all epidemiological forms of Kaposi’s sarcoma including classic, endemic, iatrogenic, epidemic and non-epidemic forms. In a Kaposi’s sarcoma lesion, KSHV is mainly in a latent state; however, a small proportion of viral particles (<5%) are in a replicative state and are reported to be potentially involved in the proliferation of neighboring cells, suggesting they have crucial roles in the process of tumorigenesis. KSHV encodes oncogenic proteins (LANA-1, v-FLIP, v-cyclin, v-GPCR, v-IL6, v-CCL, v-MIP, v-IRF, etc.) that can modulate cellular pathways in order to induce the characteristics found in all cancer, including the inhibition of apoptosis, cells’ proliferation stimulation, angiogenesis, inflammation and immune escape, and, therefore, are involved in the development of Kaposi’s sarcoma

Current and Future Tools for Diagnosis of Kaposi’s Sarcoma

International audienceKaposi’s sarcoma (KS) is a rare, atypical malignancy associated with immunosuppression and can be qualified as an opportunistic tumor, which responds to immune modulation or restoration. Four different epidemiological forms have been individualized (AIDS-related, iatrogenic, endemic or classic KS). Although clinical examination is sufficient to diagnose cutaneous lesions of KS, additional explorations are necessary in order to detect lesions involving other organs. New histological markers have been developed in recent years concerning the detection of HHV-8 latent or lytic proteins in the lesions, helping to confirm the diagnosis when it is clinically doubtful. More recently, the evaluation of the local immune response has also been shown to provide some guidance in choosing the appropriate therapeutic option when necessary. We also review the indication and the results of conventional radiological imaging and of non-invasive imaging tools such as 18F-fluoro-deoxy-glucose positron emission tomography, thermography and laser Doppler imaging for the diagnosis of KS and for the follow-up of therapeutic response in patients requiring systemic treatment

Frequency of capsid substitutions associated with GS-6207 in vitro resistance in HIV-1 from antiretroviral-naive and -experienced patients: Resistance to HIV capsid inhibitors

International audienceBackground: GS-6207 is a first-in-class HIV capsid inhibitor, targeting several functions of the HIV capsid in the viral cycle, including viral particle assembly, capsid formation and nuclear entry. GS-6207 has demonstrated picomolar potency in vitro, activity confirmed by high potency in a Phase 1 clinical study, with a long-acting antiretroviral profile with potential dosing every 6 months. In vitro resistance selections previously conducted with increasing doses of GS-6207 have identified capsid variants with reduced susceptibility to GS-6207.Objectives: To study the prevalence of capsid mutations associated with in vitro resistance to GS-6207 in people living with HIV (PLWH).Methods: Plasma samples from ART-naive or -experienced PLWH, including PI-experienced people, were sequenced and analysed for the presence of capsid variants identified during in vitro resistance selection: L56I, M66I, Q67H, K70N, N74D, N74S and T107N.Results: Among the samples from the 1500 patients studied, none of the seven GS-6207 resistance mutations identified during in vitro selection experiments was detected, regardless of HIV subtype or PLWH treatment history.Conclusions: Out of the seven HIV capsid substitutions previously selected in vitro and shown to confer phenotypic resistance to GS-6207, none of these seven mutations was observed in this large dataset, suggesting that neither PLWH with previous PI failure nor PLWH with emergence of PI resistance mutations are anticipated to impact GS-6207 activity in these diverse HIV-infected populations

Harnessing Redox Disruption to Treat Human Herpesvirus 8 (HHV-8) Related Malignancies

Reprogrammed metabolism is regarded as a hallmark of cancer and offers a selective advantage to tumor cells during carcinogenesis. The redox equilibrium is necessary for growth, spread and the antioxidant pathways are boosted following Reactive Oxygen Species (ROS) production to prevent cell damage in tumor cells. Human herpesvirus 8 (HHV-8), the etiologic agent of Kaposi sarcoma KS and primary effusion lymphoma (PEL), is an oncogenic virus that disrupts cell survival-related molecular signaling pathways leading to immune host evasion, cells growths, angiogenesis and inflammatory tumor-environment. We recently reported that primaquine diphosphate causes cell death by apoptosis in HHV-8 infected PEL cell lines in vivo and exhibits therapeutic anti-tumor activity in mice models and advanced KS. Our findings also suggest that the primaquine-induced apoptosis in PEL cells is mostly influenced by ROS production and targeting the redox balance could be a new approach to treat HHV-8 related diseases. In this review, we summarized the knowledge about the influence of ROS in cancer development; more specifically, the proof of evidence from our work and from the literature that redox pathways are important for the development of HHV-8 pathologies

M184V/I does not impact the efficacy of abacavir/lamivudine/dolutegravir use as switch therapy in virologically suppressed patients

International audienceBackground: M184V/I NRTI resistance mutations can be selected by either lamivudine/emtricitabine or abacavir. There are controversies about the use of abacavir/lamivudine/dolutegravir combinations in HIV-1-infected treatment-experienced patients with a fully suppressed HIV viral load (VL) and harbouring M184V/I.Objectives: We assessed the efficacy of abacavir/lamivudine/dolutegravir when used in HIV-infected pretreated patients with an undetectable VL who previously harboured M184V/I as a unique NRTI resistance mutation in a genotypic resistance test and had no resistance to integrase inhibitors.Patients and methods: A total of 154 patients with a fully suppressed HIV-1 plasma VL (<50 copies/mL) treated with tenofovir disoproxil fumarate/emtricitabine/boosted PI or abacavir/lamivudine/boosted PI who switched to an abacavir/lamivudine/dolutegravir regimen and had M184V/I as a unique NRTI resistance mutation in their therapeutic history were retrospectively analysed up to 12 months after the switch to abacavir/lamivudine/dolutegravir. Assessment of residual viraemia was performed at Months 1, 3, 6 and 12. Plasma VL with undetectable HIV-1 RNA corresponded to an absence of residual viraemia.Results: During the 12 months of follow-up, three patients had a blip of VL (53, 62 and 106 copies/mL) at Month 3 followed by a subsequent VL <50 copies/mL. No patient harboured a virological failure during the follow-up. Moreover, there was no change in residual viraemia during the follow-up.Conclusions: M184V/I as a unique NRTI resistance mutation, regardless of possible selection by regimens containing lamivudine/emtricitabine or abacavir, does not affect the virological response of well-controlled patients who switched to abacavir/lamivudine/dolutegravir for at least 12 months

Clinical Presentation of Covid-19 in Health Care Workers from a French University Hospital

International audienceNo abstract availabl