Catherine Dhiver

TT virus infection: prevalence of elevated viraemia and arguments for the immune control of viral load

BACKGROUND The most recent polymerase chain reaction (PCR) detection protocols for the TT virus (TTV) permit one to identify the presence of viral DNA in the serum of a majority of healthy individuals, in the absence of any particular risk factor. This is in contrast with previous epidemiological studies that reported a higher prevalence of TTV infection in populations such as haemodialysis patients (HD), haemophiliacs, intravenous drug users or diabetics. OBJECTIVES To show that these discrepant results were due to the different sensitivity (number of viral copies detected) of the detection protocols used in initial and more recent epidemiological studies. STUDY DESIGN AND RESULTS We designed a standardised primary PCR assay that detects only viraemia >5x10(3) to 5x10(4) copies/ml for genotypes 1, 2 and 3, and compared the results of this test with those of a nested PCR assay which is 100-fold more sensitive. Viraemia >5x10(3) to 5x10(4) copies/ml were statistically more frequent in HD patients (54.3%), diabetics (54.7%), and HIV-infected patients with CD4 cells <200/mm(3) (69%) than in blood donors (37%) or HIV-infected patients with CD4 cells >500/mm(3) (33%). CONCLUSIONS These data suggest a possible relationship between the prevalence of elevated viral loads and the level of immunocompetence of the populations studied, and therefore that of an immune control of TTV viraemia. This corroborates previous findings showing that the stimulation of the immune system by an interferon treatment was able to clear TTV viraemia.

Risk factors for osteonecrosis in HIV-infected patients: impact of treatment with combination antiretroviral therapy.

Background:Osteonecrosis was increasingly associated with HIV infection in the 1990s. It is unclear whether its risk increases with the duration of HIV infection, the duration of combination antiretroviral therapy (cART) or both. Objective:To analyse factors associated with the rate of symptomatic osteonecrosis, particularly the relative impacts of the duration of HIV infection and the duration of cART, using the French Hospital Database on HIV, which comprises a large number of subjects with substantial follow-up. Methods:Poisson regression model was used to identify factors associated with the rate of osteonecrosis among patients enrolled in 1996–2002. Results:The study involved 56 393 subjects with a total follow-up of 229 031 person-years. Symptomatic osteonecrosis was diagnosed in 104 subjects with an incidence rate of 4.5/10 000 person-years. Multivariate analysis identified three factors associated with the rate of osteonecrosis: prior AIDS-defining illnesses [adjusted relative rate (RR), 3.1; 95% confidence interval (CI), 2.0–4.9], the CD4 cell nadir [RR, 1.6 (95% CI, 0.9–2.9) for CD4 cell count 50–199 cells/μl; RR, 1.8 (95% CI, 1.0–3.3) for CD4 cell count < 50 cells/μl; both relative to CD4 cell count ≥ 200 cells/μl] and exposure to cART. Compared with unexposed patients, the RR of osteonecrosis ranged from 2.6 (95% CI, 1.2–5.9) in patients treated with cART for < 12 months to 5.1 (95% CI, 2.1–12.6) in patients treated for ≥ 60 months. Conclusions:Osteonecrosis appears to be a complication of both HIV infection and cART.

Antiretroviral therapy does not block the secretion of the human immunodeficiency virus tat protein.

Tat is a viral protein secreted from HIV infected cells and extra cellular Tat is suspected to prevent destruction of HIV infected cells from cells of the cellular immunity. The effect of anti retroviral therapy (ART) on Tat secretion has never been investigated. In this study, we tested for antibody reactivity against Tat variants representative of the main HIV subtypes in HIV positive patients receiving ART with undetectable viral loads ( < 40 copies/mL) over the course of one year with a blood sampling every three months. For each of theses five blood sampling, an average of 50 % of patients had Anti-Tat IgG, it turned out that 86% of patients could recognize Tat at least in one blood sampling during the course of the study. Amazingly, anti-Tat IgG appeared and/or disappeared in 66 % of patients. Only 20% had anti-Tat IgG remaining persistently while 14% were consistently without anti Tat IgG in the five blood sampling. No significant correlation was found between anti-Tat IgG and CD4+ T cell, CD8+ T cell and B cell counts revealing the incapacity of these anti Tat IgG to neutralize extra cellular Tat. Interestingly the absence and then the appearance of anti-Tat IgG in patients suggest the presence of HIV infected cells in the blood that may constitute a significant reservoir of HIV infected cells. As a conclusion antiretroviral therapy does not block the secretion of Tat and may explain why HIV infected cells can survive in spite of an effective ART treatment.

Successful treatment with sofosbuvir of fibrosing cholestatic hepatitis C after liver transplantation in an HIV-HCV-coinfected patient.

Fibrosing cholestatic hepatitis is a severe form of post-liver transplantation HCV recurrence. Fibrosing cholestatic hepatitis is characterized by its early onset and severe prognosis in HIV-infected patients. We report the case of an HIV-HCV genotype-4 coinfected patient successfully treated with a combination of sofosbuvir and ribavirin. After 4 weeks of treatment we observed a resolution of HCV recurrence related symptoms associated with a normalization of liver biochemistry and dramatic decrease of HCV viral load. This case illustrates the efficiency and tolerance of a sofosbuvir-based anti-HCV interferon-free regimen in post-liver HCV recurrence. Because of the absence of drug interactions between sofosbuvir and antiretroviral treatment or calcineurin inhibitors, its administration in HIV-HCV-coinfected liver transplanted patients is very promising.

Dolutegravir and weight gain: an unexpected bothering side effect?

We recently analyzed, in our real-life cohort of 2260 HIV-infected patients, the reasons for discontinuation of dolutegravir-based combined antiretroviral therapies (cARTs) [1]. Of 517 patients, 55 (10.6%) discontinued this cART due to adverse effects. Unexpectedly, four (7%) of these adverse effect

Feasibility and Acceptability of Anal Self-Sampling for Human Papillomavirus Screening in HIV-Infected Patients

Objectives: Anal cancer incidence is increasing among HIV-positive patients. No consensus currently exists for the screening of anal dysplasia. This study aimed at evaluating the feasibility and acceptability of anal self-sampling and assessing the prevalence of human papillomavirus (HPV) types among HIV-positive patients from Marseille University Hospitals. Methods: Between October 2013 and March 2014, during their regular visits for the monitoring of their HIV infection in an HIV outpatient clinical unit of Marseille University Hospitals, patients were asked to self-sample anal swabs for HPV detection. A specimen self-collection kit was provided. HPV detection and genotyping were performed using in-house protocols. The quality of self-sampling was assessed by concurrent cellular quantification in collected samples. Results: The acceptability rate of anal self-sampling was 91%, and 91% of the self-sampled specimens were appropriate for HPV screening. In addition, 76% of the samples were positive for HPV, including 54% of HPV types with oncogenic potential. Conclusions: This study indicates that HPV detection and typing through anal self-sampling is a valuable strategy to screen patients at high risk for anal cancer development. This could allow earlier management of anal lesions and related cancer in patients at high risk for HPV.

Hepatitis C virus NS3 protease genotyping and drug concentration determination during triple therapy with telaprevir or boceprevir for chronic infection with genotype 1 viruses, southeastern France

Telaprevir and boceprevir, the two first hepatitis C virus (HCV) NS3 protease inhibitors (PIs), considerably increase rates of sustained virologic response in association with pegylated interferon and ribavirin in chronic HCV genotype 1 infections. The 30 first patients treated by telaprevir or boceprevir including anti‐HCV therapies since 2011 in Marseille University hospitals, France, were monitored. HCV loads and plasmatic concentrations of telaprevir and boceprevir were determined on sequential blood samples. HCV NS3 protease gene population sequencing was performed at baseline of treatment and in case of treatment failure. Fifteen patients (including 7 co‐infected with HIV) received telaprevir and the other 15 patients (including 4 co‐infected with HIV) received boceprevir. At baseline, HCV NS3 protease from six patients harbored amino acid substitutions associated with PI‐resistance. Treatment failure occurred at week 12 for 7 patients. Amino acid substitutions associated with PI‐resistance were observed in six of these cases. HCV NS3 R155K and T54A/S mutants, all of genotype 1a, were found from four patients. Median (interquartile range) plasma concentrations were 3,092 ng/ml (2,320–3,525) for telaprevir and 486 ng/ml (265–619) for boceprevir. For HIV–HCV co‐infected patients, median concentrations were 3,162 ng/ml (2,270–4,232) for telaprevir and 374 ng/ml (229–519) for boceprevir. Plasma drug concentration monitoring revealed undetectable concentrations for two patients at week 4, and probable non‐adherence to therapy for another patient. These findings indicate that routine HCV NS3 protease sequencing and plasma PI concentration monitoring might be helpful to characterize cases of therapy failure, at a cost dramatically low compared to that of anti‐HCV therapy. J. Med. Virol. 86:1868–1876, 2014.

Evaluation of self-collected rectal swabs for the detection of bacteria responsible for sexually transmitted infections in a cohort of HIV-1-infected patients

Purpose. The standard approach to screening sexually transmitted infections (STIs) has often been restricted to urogenital specimens. Most current guidelines, however, also recommend testing extra‐genital sites, including rectal locations, because asymptomatic rectal carriage of pathogens has often been reported. The aim of our study was to evaluate self‐collected rectal swabs to screen bacterial STIs in HIV‐infected patients in Marseille, France. Methodology. Between January 2014 and December 2015, 118 HIV‐infected patients (93 males and 25 females) agreed to self‐sample anal swabs for detection of bacterial STI. Detection of Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, Mycoplasma genitalium and Haemophilus ducreyi was performed using in‐house qPCR assay. Results/Key findings. Bacterial STIs were found in 8% (9/118) of the patients. C. trachomatis was the most commonly detected bacterium (4.2%) followed by N. gonorrhoeae (2.5%), M. genitalium (1.7%) and T. pallidum (0.8%). All the positive patients were males. The rectal carriage of pathogenic bacteria was fortuitously discovered for seven men (78%) who did not present rectal signs of STIs and was suspected for two men who presented proctitis (22%). Conclusion. In conclusion, testing extra‐genital sites is crucial for the diagnosis of STIs in men and women presenting or not concomitant urogenital infections in order to detect asymptomatic carriage with the aim of controlling and preventing transmission to their sexual partners.

Recombinant hepatitis C viruses that might hamper accurate genotype classification and choice of treatment with direct-acting agents, southeastern France.

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Toward chronic hepatitis C eradication in HIV-positive patients, including those cirrhotic and infected with genotype 3 viruses

Direct-acting agents (DAA) have proved dramatic efficiency to cure chronic hepatitis C.1 ,2 Extensive assessment of their real-life effectiveness is now required, including in cirrhotic and genotype 3 HCV-infected patients who are under-represented in real-world studies but are considered the still hard-to-cure population.1–5 We read therefore with interest the article by Welzel et al 1 about the achievement of sustained virological response (SVR) in 91% of cases in a real-world cohort treated with sofosbuvir plus daclatasvir with or without ribavirin for 12–24 weeks. Indeed, remarkably, SVR was 92% in patients infected with HCV-3 (n=102), 97% in cirrhotics (n=389), 98% in HIV-infected individuals (n=55) and 96% in case of prior HCV therapy (n=341). We analysed the efficacy and safety of DAA-based anti-HCV therapies administered during 2 years (May 2014–April 2016) to a real-world cohort of 170 HCV-HIV-coinfected …