[French research organization on emerging infectious diseases: From REACTing to ANRS emerging infectious diseases]. / La recherche française face aux maladies infectieuses émergentes : de REACTing à l'ANRS- maladies infectieuses émergentes.

Emerging infectious diseases (EIDs) can be responsible for epidemics or even pandemics that disrupt societies and cause national and international crises. In our globalized world, anarchic urbanization, ecosystem disruptions (deforestation, creation of dams…), changes in crop and livestock farming conditions, the increasing availability of air transport, population displacement and climate change are all factors that favor the occurrence and spread of emerging or re-emerging pathogens such as SARS-Cov, MERS-CoV, Ebola, Zika, influenza, or more recently SARS-CoV-2 and Monkeypox. States, regional and international organizations, health and research agencies, non-governmental organizations and the pharmaceutical industry are today challenged by the repetition of these crises and their consequences on health, social, economic and political balances. For the past fifteen years, we have clearly been in a new regime of infectious emergence and re-emergence. This new regime calls for new responses, to meet in the urgency the challenges of emergency epidemic crises and to better respond to the issues of crisis management in a context of "One Health". Research is an essential pillar in the response to these epidemics with a double challenge: (i) to improve knowledge on the disease, its prevention, treatment, diagnosis, impact on society. and (ii) to prepare for and understand future emergencies, "anticipate". As epidemics have occurred over the last fifteen years, French research has been organized and has evolved to respond to these crises, from the genesis of REACTing in 2011, to the creation of the ANRS Emerging Infectious Diseases in 2021.

HIV-1 subtype influences susceptibility and response to monotherapy with the protease inhibitor lopinavir/ritonavir.

OBJECTIVE: PI susceptibility results from a complex interplay between protease and Gag proteins, with Gag showing wide variation across HIV-1 subtypes. We explored the impact of pre-treatment susceptibility on the outcome of lopinavir/ritonavir monotherapy. METHODS: Treatment-naive individuals who experienced lopinavir/ritonavir monotherapy failure from the MONARK study were matched (by subtype, viral load and baseline CD4 count) with those who achieved virological response ('successes'). Successes were defined by viral load <400 copies/mL after week 24 and <50 copies/mL from week 48 to week 96. Full-length Gag-protease was amplified from patient samples for in vitro phenotypic susceptibility testing, with susceptibility expressed as fold change (FC) relative to a subtype B reference strain. RESULTS: Baseline lopinavir susceptibility was lower in viral failures compared with viral successes, but the differences were not statistically significant (median lopinavir susceptibility: 4.4 versus 8.5, respectively, P = 0.17). Among CRF02_AG/G patients, there was a significant difference in lopinavir susceptibility between the two groups (7.1 versus 10.4, P = 0.047), while in subtype B the difference was not significant (2.7 versus 3.4, P = 0.13). Subtype CRF02_AG/G viruses had a median lopinavir FC of 8.7 compared with 3.1 for subtype B (P = 0.001). CONCLUSIONS: We report an association between reduced PI susceptibility (using full-length Gag-protease sequences) at baseline and subsequent virological failure on lopinavir/ritonavir monotherapy in antiretroviral-naive patients harbouring subtype CRF02_AG/G viruses. We speculate that this may be important in the context of suboptimal adherence in determining viral failure.

Progressive contraction of the latent HIV reservoir around a core of less-differentiated CD4⁺ memory T Cells.

In patients who are receiving prolonged antiretroviral treatment (ART), HIV can persist within a small pool of long-lived resting memory CD4(+) T cells infected with integrated latent virus. This latent reservoir involves distinct memory subsets. Here we provide results that suggest a progressive reduction of the size of the blood latent reservoir around a core of less-differentiated memory subsets (central memory and stem cell-like memory (TSCM) CD4(+) T cells). This process appears to be driven by the differences in initial sizes and decay rates between latently infected memory subsets. Our results also suggest an extreme stability of the TSCM sub-reservoir, the size of which is directly related to cumulative plasma virus exposure before the onset of ART, stressing the importance of early initiation of effective ART. The presence of these intrinsic dynamics within the latent reservoir may have implications for the design of optimal HIV therapeutic purging strategies.

Very prolonged liposomal amphotericin B use leading to a lysosomal storage disease.

Amphotericin B is a powerful polyene antifungal drug used for treating systemic fungal infections and is usually administered for a short period. Side effects after prolonged use are unknown in humans. Here we report the case of a 28-year-old man suffering from chronic granulomatous disease (CGD), treated for invasive cerebral aspergillosis with liposomal amphotericin B (L-AmB) for a very long time (8 consecutive years). We describe the efficacy and safety of this treatment in the long term. Aspergillosis was kept under control as long as L-AmB therapy was maintained, but relapsed when the dose was reduced. No overt renal toxicity was noted. The patient gradually developed hepatosplenomegaly and pancytopenia. Abnormalities of bone marrow were similar to the sea-blue histiocyte syndrome. Liver biopsy showed images of nodular regenerative hyperplasia related to CGD as well as a histiocytic storage disease. We discuss the very prolonged use of L-AmB leading to the development of a lysosomal storage disease.

Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study.

BACKGROUND: The immune deficiency of human immunodeficiency virus (HIV) infection is not fully corrected with ARV therapy. Interleukin-7 (IL-7) can boost CD4 T-cell counts, but optimal dosing and mechanisms of cellular increases need to be defined. METHODS: We performed a randomized placebo-controlled dose escalation (10, 20 and 30 µg/kg) trial of 3 weekly doses of recombinant human IL-7 (rhIL-7) in ARV-treated HIV-infected persons with CD4 T-cell counts between 101 and 400 cells/µL and plasma HIV levels <50 copies/mL. Toxicity, activity and the impact of rhIL-7 on immune reconstitution were monitored. RESULTS: Doses of rhIL-7 up to 20 µg/kg were well tolerated. CD4 increases of predominantly naive and central memory T cells were brisk (averaging 323 cells/µL at 12 weeks) and durable (up to 1 year). Increased cell cycling and transient increased bcl-2 expression were noted. Expanded cells did not have the characteristics of regulatory or activated T cells. Transient low-level HIV viremia was seen in 6 of 26 treated patients; modest increases in total levels of intracellular HIV DNA were proportional to CD4 T-cell expansions. IL-7 seemed to increase thymic output and tended to improve the T-cell receptor (TCR) repertoire in persons with low TCR diversity. CONCLUSIONS: Three weekly doses of rhIL-7 at 20 µg/kg are well tolerated and lead to a dose-dependent CD4 T-cell increase and the broadening of TCR diversity in some subjects. These data suggest that this rhIL-7 dose could be advanced in future rhIL-7 clinical studies. CLINICAL TRIALS REGISTRATION: NCT0047732.

Single-nucleotide polymorphism-defined class I and class III major histocompatibility complex genetic subregions contribute to natural long-term nonprogression in HIV infection.

We performed a genome-wide association study comparing a cohort of 144 human immunodeficiency virus (HIV type 1-infected, untreated white long-term nonprogressors (LTNPs) with a cohort of 605 HIV-1-infected white seroconverters. Forty-seven single-nucleotide polymorphisms (SNPs), located from class I to class III major histocompatibility complex (MHC) subregions, show statistical association (false discovery rate, <0.05) with the LTNP condition, among which 5 reached genome-wide significance after Bonferonni correction. The MHC LTNP-associated SNPs are ordered in ≥4 linkage disequilibrium blocks; interestingly, an MHC class III linkage disequilibrium block (defined by the rs9368699 SNP) seems specific to the LTNP phenotype.

[Enhancing immune restoration in human immunodeficiency virus infection]. / Stratégies de restauration immunitaire chez les patients infectés par le virus de l'immunodéficience humaine.

The primary objective of antiretroviral therapy has recently evolved from a virologic endpoint towards the achievement of normal CD4T cell count (greater than 500/mm(3)) to avoid progression to AIDS. This shift in the primary objective is supported by many clinical and epidemiological studies. Recent data have shown that HIV-infected adults with a CD4T cell count greater than 500cells/mm(3) on long-term combination antiretroviral therapy reach same mortality rates as the general population. However, less than 50% of patients receiving long-term suppressive antiretroviral combination reach such a CD4T cell level. New antiretroviral strategies to improve immune reconstitution, such as specific or non-specific immune-based therapy on one hand and the use of novel antiretroviral drugs from new classes on the other hand are currently under investigation. Here we review several current strategies that may improve immune reconstitution, keeping in mind that the best way to reach normal CD4T cell count is an early treatment initiation.

Prospective one-year bone loss in treatment-naïve HIV+ men and women on single or multiple drug HIV therapies.

Antiretroviral therapy has decreased the rate of HIV-related mortality and extended the life span of HIV patients. Current guidelines recommend the use of a 3-drug regimen, such as two nucleoside reverse transcriptase inhibitors and a protease inhibitor, boosted by ritonavir. Osteoporosis can be associated with the HIV disease itself or with antiretroviral therapy. Many trials have been conducted employing a single drug regimen to simplify antiretroviral therapy but few studies assessed the effect of the single drug regimen on bone mineral density (BMD). The objectives of the study were to assess and compare the relative (%) changes in lumbar spine and hip BMD over 48 weeks in HIV patients treated with mono or triple antiretroviral regimens The study was conducted using data from a randomized trial (MONARK) conducted in 136 antiretroviral-naïve HIV patients (89 men and 47 women) comparing the antiviral efficacy of a single-drug protease inhibitor regimen of lopinavir/ritonavir (LPV/r) versus LPV/r in combination with zidovudine (ZDV) and lamivudine (3TC). Lumbar spine and total hip BMD were assessed in 100 patients by dual-energy X-ray absorptiometry at baseline and 48 weeks. 48 week-BMD data were available for 43 patients (mean age 37years) with a mean baseline lumbar spine Z-score of -0.1 in the LPV/r monotherapy group and for 25 patients (mean age 35.8years) with a mean baseline lumbar spine Z-score of -0.2 in the LPV/r+ZDV+3TC group. After 48weeks, lumbar spine BMD significantly decreased by 4.4% (-5.1% to -2.1%, P≤0.001) in the LPV/r group and by 4.0% (-5.0% to -1.7%, P≤0.0001) in the LPV/r+ZDV+3TC group. There was no significant difference in BMD changes between the two groups. These results suggest that bone loss is observed 48 weeks after the initiation of antiretroviral therapy, whether the patients receive a single- or triple-drug antiretroviral regimen.

[Pandemic influenza A/H1N1v, pregnancy and vaccination]. / Pandémie grippale A/H1N1v, grossesse et vaccination.

Seasonal flu is potentially more severe during pregnancy especially when it occurs in the last three months. Pregnant women were shown to be especially exposed to severe forms of the flu and death in the first weeks of the pandemic influenza A/H1N1v. For the first time in history, adequate vaccines were available in the early phase of the pandemic and recommended by WHO as a priority for pregnant women. In France, vaccination with the non-adjuvanted vaccine (Panenza®) was recommended after three months of pregnancy. However, the pandemic vaccines were discredited by the mass media and the population even before they were available. This was due to several factors, and especially to the lack of information on the vaccine and its potential toxicity and, in case of pregnancy, potential risk of adverse fetal events, despite the fact that available data shows the seasonal flu vaccine is effective and well tolerated in pregnant women. This article aimed to provide decisional elements for influenza A/H1N1v vaccination in pregnant women.

Breast enlargement in an HIV-infected man on combined antiretroviral therapy: what if it was carcinoma?

We describe a case of an HIV-infected man on effective combined antiretroviral therapy, presenting with bilateral gynaecomastia revealing breast carcinoma. Gynaecomastia was first considered to be related to efavirenz and/or didanosine. Although breast carcinoma is rare among HIV-infected men, it should be considered as a potential cause of breast enlargement.

Long-term (96-week) follow-up of antiretroviral-naïve HIV-infected patients treated with first-line lopinavir/ritonavir monotherapy in the MONARK trial.

BACKGROUND: The toxicities, cost and complexity of triple combinations warrant the search for other treatment options, such as boosted protease inhibitor (PI) monotherapy. MONotherapy AntiRetroviral Kaletra (MONARK) is the first randomized trial comparing lopinavir/ritonavir monotherapy to triple combination therapy with zidovudine/lamivudine and lopinavir/ritonavir in antiretroviral-naïve patients. METHODS: A total of 136 antiretroviral-naïve patients, with a CD4 cell count above 100 cells/microL and a plasma HIV RNA below 100,000 HIV-1 RNA copies/mL, were randomized and dosed with either lopinavir/ritonavir monotherapy (n = 83) or lopinavir/ritonavir + zidovudine/lamivudine (n = 53). We focus here on patients in the lopinavir/ritonavir monotherapy arm followed to week 96. The intent-to-treat (ITT) analysis initially involved all patients randomized to lopinavir/ritonavir monotherapy (n = 83), and then focused on patients who had an HIV RNA < 50 copies/mL at week 48 (n = 56). RESULTS: At week 96, 39 of 83 patients (47%) had HIV RNA < 50 copies/mL, five of 83 had HIV RNA between 50 and 400 copies/mL, and three of 83 had HIV RNA > 400 copies/mL. Focusing on the 56 patients with an HIV RNA < 50 copies/mL at week 48, 38 of 56 patients (68%) had a sustained HIV RNA < 50 copies/mL to week 96. To week 96, a total of 28 patients (34%) had discontinued the study treatment. In addition, the allocated treatment was changed for seven patients. PI-associated resistance mutations were evident in five of 83 patients in the monotherapy arm from baseline to week 96. CONCLUSION: By ITT analysis, 39 of the 83 patients initially randomized to lopinavir/ritonavir monotherapy had HIV RNA < 50 copies/mL at week 96. The occurrence in some patients of low-level viraemia (50-500 copies/mL) may increase the risk of drug resistance. First-line lopinavir/ritonavir monotherapy cannot be systematically recommended.

[Autoimmune myelofibrosis with dermatomyositis]. / Myélofibrose auto-immune secondaire à une dermatomyosite.

We report a second observation of autoimmune myelofibrosis associated with an inflammatory myositis in a 30-year-old female. The links between myelofibrosis and autoimmunity are discussed.

Improved virological response to highly active antiretroviral therapy in HIV-1-infected patients carrying the CCR5 Delta32 deletion.

BACKGROUND: Patients heterozygous for the C-C chemokine receptor 5 (CCR5) Delta32 deletion spontaneously progress less rapidly to AIDS and death than do wild-type patients. We investigated whether the CCR5 Delta32 deletion has an impact on immunological, virological and clinical responses to highly active antiretroviral therapy (HAART) in HIV-1-infected patients. PATIENTS AND METHODS: We included in the study 565 HIV-1-infected patients from the French HIV-1 infected cohort with documented date of seroconversion (SEROCO)/haemophiliacs HIV-1 infected (HEMOCO) cohorts, who started HAART after 1996. We investigated virological responses to HAART at 6 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection or a 2 log HIV-1 RNA decrease) and at 12 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection) and clinical response to HAART by Kaplan-Meier survival curves, with AIDS and death as outcomes. RESULTS: The Delta32 heterozygous patients (n=83; 15%) had a better virological response to HAART than wild-type patients (73 vs 53% at 6 months, P=0.01; and 60 vs 44% at 12 months, P=0.01). This better virological response was still observed after adjustment for antiretroviral status (whether or not patients were naïve to antiretroviral therapy), year of HAART initiation, number of new antiretroviral drugs and baseline viral load. There was no statistical difference between heterozygous patients and wild-type patients in terms of survival and AIDS-free survival. CONCLUSIONS: CCR5 Delta32 heterozygous patients were more likely to have a virological response to HAART than wild-type patients at 6 and 12 months. However, this virological response did not produce better immunological and clinical responses. The long-term impact of the Delta32 deletion on survival in HIV-1-infected treated patients should be investigated in a meta-analysis.

[Actinomyces odontolyticus isolation during prosthetic aortic graft infection with paraprosthetic duodenal fistula]. / Isolement d'Actinomyces odontolyticus au cours d'une infection de prothèse aortique avec fistule duodénoparaprothétique.

INTRODUCTION: Prosthetic vascular graft infection is a rare complication of vascular surgery. We report a case with graft enteric fistula and Actinomyces odontolyticus bacteremia. EXEGESIS: A 73 year-old man with a prosthetic aortic graft and who had a parodontal disease, has been hospitalised for fever of unknown origin. Blood cultures grew with Escherichia coli and Actinomyces odontolyticus. The imaging studies indicated graft infection. Laparotomy has confirmed the diagnosis and highlighted a polymicrobial infection and a paraprosthetic duodenal fistula. A review of the literature's data concerning prosthetic vascular graft infections is made. The role of Actinomyces odontolyticus in that case is discussed. CONCLUSION: Prosthetic aortic graft infection due to graft enteric fistula is usually a polymicrobial infection and is a late complication of aortic surgery. Imaging is essential for the diagnosis of prosthetic aortic graft infection. It is possible that Actinomyces odontolyticus has contributed to prosthesis infection in this case.

Constant mitochondrial DNA levels in blood leukocytes of patients enrolled in a NRTI-free therapeutic trial (BIKS-2 study).

OBJECTIVES: Determine if a nucleoside reverse transcriptase inhibitors (NRTI)-free regimen affected mitochondrial DNA (mtDNA) levels in peripheral blood mononuclear cells (PBMCs) of patients enrolled in BIKS-2 trial. METHODS: Antiretroviral (ARV) naïve (N=13) and NRTI experienced (N=7) patients, received lopinavir/ritonavir, a boosted protease inhibitor, and efavirenz, a non-nucleoside reverse transcriptase inhibitor from Month (M) 0 to M12 (1-year BIKS trial) and from M12 to M36 (2-year BIKS-2 trial). MtDNA was quantified at M12, M24 and M36 via real-time PCR assay. RESULTS: From M12 to M36, the 20 patients have maintained undetectable plasma HIV-1 RNA, gained CD4 cells and had no side effects attributable to these drugs. Median mtDNA contents were constant: 478.6 at M12, 478.6 at M24 and 324.4 copies/cell at M36 (pM12-M36=0.5). Because M0 data is missing, these results were compared to those of two groups of age matched individuals: healthy donors and HIV-infected patients before and after exposure to NRTIs. Healthy donors have higher contents (871), followed by patients never treated (602), than by BIKS patients where 7 had toxic NRTIs (478.6) and at last by patients exposed for six months to the most toxic combination (ddI-d4T) (85 copies/cell). CONCLUSION: Lopinavir/ritonavir+efavirenz did not affect mtDNA contents in PBMCs.