[Hepatitis C in a psychiatric setting: A forgotten reservoir?] / Hépatite C en milieu psychiatrique : un réservoir oublié ?

Hepatitis C is a transmissible hepatic and extra-hepatic disease caused by the hepatitis C virus (HCV). HCV develops into a chronic infection among approximately 70% of the contaminated subjects. Chronic HCV infection is estimated to affect between 0.5% and 1 % of the general population in France, which causes an important burden of disease, in particular due to the occurrence of cirrhosis and liver cancer. New antiviral drugs now allow to cure more than 95% of patients in just a few weeks of treatment with very limited safety issues. This therapeutic revolution has led the World Health Organization and many national governments to aim for an elimination of HCV, which has been defined as a 90%-reduction of the incidence rate, and a 65%-reduction in the number of HCV-related deaths on the basis of the 2015 figures. In this respect, the French Ministry of Health has recently decided to extend the ability to prescribe the new antiviral drugs to any physician. However, the elimination campaign of HCV will also need to correctly identify, screen, and treat the main target populations. If people who inject drugs (PWIDs) certainly constitute the most important population concerned by the challenge of HCV elimination, more hidden reservoirs in which HCV transmission can insidiously evolve should be identified and specifically targeted as well. Inpatient psychiatric populations might constitute one of these hidden reservoirs. International data suggest that chronic HCV infection affects approximately 5% of psychiatric inpatients in Europe. This very high prevalence estimate can in part be due to the very frequent psychiatric disorders found among the current or former PWIDs. However, a part of the seropositive patients does not report a history of drug use, and other factors could contribute to the increased risk of contamination in this population including atypical routes of transmission related to institutional promiscuity. Exploring the general profile and risk-behaviors of the psychiatric inpatients found infected by the HCV is thus warranted for future studies. Screening and treating HCV in the specific population of psychiatric patients is part of the general public health objective of eliminating HCV at a national level. Moreover, it also directly fits into the individualized psychiatric care. Many recent data suggest that HCV also has a neural tropism, in particular within glial cells, such as astrocytes or oligodendrocytes. As such, HCV foments inflammatory processes in the brain and contributes to cognitive impairments and psychiatric symptoms such as anxiety or depression. At the individual level, treating HCV infection can improve the psychiatric state and increase patients' outcomes in terms of well-being and quality of life. For all these reasons, the field of psychiatry needs local and national actions for informing and training professionals about HCV screening and treating modalities. Patient and family associations also need to be involved in this general effort of micro-elimination. A key role should be assigned to the general practitioners embedded within inpatient psychiatric units. They are the best fitted professionals to screen, treat, and empower patients, to inform and train other caregivers of the psychiatric field, and to act as a relay with hepatology teams if required. Hospital pharmacists are other important stakeholders. In a national context in which the funding of psychiatric care, including medications, is based on predefined funding envelops, innovative initiatives will have to be set up by local or national health authorities, in partnership with pharmacists, to allow for the treatment of psychiatric inpatients. In conclusion, the world of psychiatry is a possible hidden reservoir of HCV and, as such, a part of the challenge for eliminating the virus. Patients, families, and caregivers will have to be correctly sensitized and trained to play their role in the process. Specific investigations will be required to better understand why such an increased prevalence of HCV is observed in this population. Specific adaptations of the cascade of care within psychiatric settings, including access to treatment, will need to be designed, implemented, and evaluated for reaching micro-elimination of HCV in psychiatry.

Efficacy, safety and patient-reported outcomes of ledipasvir/sofosbuvir in NS3/4A protease inhibitor-experienced individuals with hepatitis C virus genotype 1 and HIV coinfection with and without cirrhosis (ANRS HC31 SOFTRIH study).

OBJECTIVES: Studies evaluating the efficacy and safety of the fixed-dose combination ledipasvir (LDV)/sofosbuvir (SOF) in patients coinfected with HIV-1 and hepatitis C virus (HCV) have mainly included treatment-naïve patients without cirrhosis. We aimed to evaluate the efficacy and safety of this combination in treatment-experienced patients with and without cirrhosis. METHODS: We conducted a multicentre, open-label, double-arm, nonrandomized study in patients coinfected with HIV-1 and HCV genotype 1 with and without cirrhosis, who had good viral suppression on their antiretroviral regimens. All patients were pretreated with a first-generation NS3/4A protease inhibitor (PI) plus pegylated interferon/ribavirin. Patients received a fixed-dose combination of LDV/SOF for 12 weeks, or for 24 weeks if cirrhosis was present. The primary endpoint was a sustained virological response (SVR) 12 weeks after the end of therapy. Secondary endpoints included safety, pharmacokinetics and patient-reported outcomes. RESULTS: Of the 68 patients enrolled, 39.7% had cirrhosis. Sixty-five patients [95.6%; 95% confidence interval (CI): 87.6-99.1%; P < 0.0001] achieved an SVR, with similar rates of SVR in those with and without cirrhosis. Tolerance was satisfactory, with mainly grade 1 or 2 adverse events. Among patient-reported outcomes, only fatigue significantly decreased at the end of treatment compared with baseline [odds ratio (OR): 0.36; 95% CI: 0.14-0.96; P = 0.04]. Mean tenofovir area under the plasma concentration-time curve (AUC) at week 4 was high, with mean ± SD AUC variation between baseline and week 4 higher in cirrhotic than in noncirrhotic patients (3261.57 ± 1920.47 ng/mL vs. 1576.15 ± 911.97 ng/mL, respectively; P = 0.03). Mild proteinuria (54.4%), hypophosphataemia (50.0%), blood bicarbonate decrease (29.4%) and hypokalaemia (13.2%) were reported. The serum creatinine level was not modified. CONCLUSIONS: LDV/SOF provided a high SVR rate in PI-experienced subjects coinfected with HCV genotype 1 and HIV-1, including patients with cirrhosis.

Recent evidence of underestimated circulation of hepatitis C virus intergenotypic recombinant strain RF2k/1b in the Rhône-Alpes region, France, January to August 2014: implications for antiviral treatment.

Since the beginning of 2014, hepatitis C virus (HCV) recombinant forms RF2k/1b have been detected in the Rhône-Alpes French region in 10 patients originating from the Caucasus area. Circulation of this particular HCV strain is very likely to be underestimated. It is also prone to be misgenotyped when using genotyping methods based on the 5' region of the viral genome, which may lead to suboptimal treatment.

Boceprevir and telaprevir-based triple therapy for chronic hepatitis C: virological efficacy and impact on kidney function and model for end-stage liver disease score.

Triple therapy using telaprevir or boceprevir [hepatitis C virus (HCV)-NS3/NS4A protease inhibitors (PI)] in association with PEG-IFN/ribavirin has recently become the new standard of care (SOC) for treatment of HCV genotype 1 patients. Our objective was to assess the efficacy and tolerance of triple therapy in routine clinical practice. A total of 186 consecutive HCV patients initiating triple therapy were enrolled in a single centre study. Clinical, biological and virological data were collected at baseline and during follow-up as well as tolerance and side effect details. Among 186 HCV patients initiating triple therapy, 69% received telaprevir and 31% boceprevir. Sixty-one per cent of patients had cirrhosis. The overall extended rapid virological response (eRVR) rate and sustained virological response (SVR) rate were 57.0% and 59.7%, respectively. IL28B CC phenotype was associated with increased probability of achieving eRVR and SVR, whereas previous non-response was associated with low eRVR and SVR rates. The SVR rate increased from 30.8% in previously non-responders to 59.1% in partial non-responders and 75% in relapsers. SVR rate in naive patients was 62.5%. Glomerular filtration rate assessed by MDRD after 12 weeks of therapy was significantly reduced for both PI (P < 0.001). The model for end-stage liver disease (MELD) score was significantly increased at W12 for telaprevir (P = 0.008) and at W24 for boceprevir (P = 0.027). PI-based triple therapy leads to high rates of virological response even in previously non-responder patients. Renal function after triple therapy is impaired as well as MELD score in all patients. Cautious clinical monitoring should focus not only on haematological and dermatological side effects but also on renal function.

Inflammatory pain pattern and pain with lumbar extension associated with Modic 1 changes on MRI: a prospective case-control study of 120 patients.

PURPOSE: To compare, in a case-control study, clinical characteristics of patients with low back pain (LBP) with and without Modic 1 signal changes on MRI. METHODS: Patients with chronic non-specific LBP and a recent (<6 months) MRI were prospectively screened and included in Modic 1 group or control group. Patients in control group were age- and gender-matched with patients with Modic 1 group. Pain characteristics, including night pain and worse pain on waking and morning stiffness, were recorded. The presence of at least one of these three characteristics indicated an inflammatory pain pattern. Patients were evaluated by questionnaires and physical examination (including lumbar range of motion). Data were analyzed by univariate and multivariate analyses. RESULTS: 120 patients were included (60 in each group). The groups did not differ in sedentary work (p = 0.25), morning stiffness for >60 min (p = 0.19), waking at night (p = 0.08), worse pain on waking (p = 0.09), back stiffness (p = 0.12), or pain with flexion (p = 0.87). Modic 1 patients more frequently exhibited an inflammatory pain pattern (p = 0.006), worse pain with lumbar extension (p < 0.005) and responded better to oral steroids (p = 0.004) than did controls. On multivariate analysis, Modic 1 changes were associated with sedentary work [odds ratio 0.22 (95% confidence interval 0.05-0.93)], pain with lumbar extension [11.2 (3.1-40.4)] and an inflammatory pain pattern [4.5 (1.2-16.9)]. CONCLUSIONS: Characteristics of patients with LBP and Modic 1 changes on MRI consist of an inflammatory pain pattern and pain with lumbar extension. Level of evidence 3b.

Evolution of glomerular filtration rate in HIV-infected, HIV-HBV-coinfected and HBV-infected patients receiving tenofovir disoproxil fumarate.

We aimed to compare the evolution of estimated glomerular filtration rate (eGFR) in HIV-, HIV-HBV- and HBV-infected patients treated with tenofovir disoproxil fumarate (TDF). Three groups of patients receiving TDF > 12 months were recruited: 194 HIV-infected patients, 85 HIV-HBV-coinfected patients and 50 HBV-infected patients. eGFR was estimated using the Modification of the Diet in Renal Disease (MDRD) equation. Multivariate regression models were constructed to estimate factors associated with eGFR decrease from baseline. A total of 329 patients were studied. Median follow-up was 2.7 years. Median eGFR decrease was -4.9 (-16.6 to +7.2) mL/min/1.73 m(2) . After multivariate stepwise regression analysis, age (P = 0.0002), non-African origin (P < 0.0001), baseline eGFR (P < 0.0001) and TDF duration (P = 0.02) were associated with eGFR decrease in the whole population, while hypertension, diabetes and type of infection were not. Age (P < 0.0001), non-African origin (P = 0.0004), baseline eGFR (P < 0.0001) and TDF duration (P = 0.007) remained associated with eGFR decline in HIV and HIV-HBV-infected patients, while other variables including HIV risk factor, CDC stage, CD4 and HIV-RNA levels were not. Age (P = 0.03), non-African origin (P = 0.004), baseline eGFR (P < 0.0001) and baseline HBV-DNA > 2000 IU/mL (P = 0.04) were associated with eGFR decline in HBV and HIV-HBV-infected patients, while other variables including HBV risk factor and fibrosis stage were not. Estimated glomerular filtration rate decline under TDF therapy appears mainly associated with older age, non-African origin, higher baseline eGFR and longer TDF administration but not with the type of viral infection. Regular follow-up of renal function, especially tubular function is recommended during TDF therapy.

New approaches to the management of hepatitis C in haemophilia in 2012.

Hepatitis C virus (HCV) infection is common in patients with Haemophilia. As in other patients, its natural history is characterized by disease progression towards cirrhosis and hepatocellular carcinoma. Many patients with hereditary bleeding disorders infected with HCV are also infected with HIV which is a factor of faster liver disease progression. In the past years, major progress has been made in the management of hepatitis C with the development of non invasive tools to assess liver fibrosis stage, i.e. fibroscan and biomarkers. With these tools, it is now possible to predict with good accuracy the liver disease stage and to take treatment decision. The landscape of antiviral therapy has evolved rapidly, especially for patients infected with HCV genotype 1. Triple therapy with interferon, ribavirin and protease inhibitors has been approved recently, the results of clinical trials showing a clear added benefit in terms of sustained virologic response in naive patients compared to interferon - ribavirin combination therapy. However, results are less promising in cirrhotic patients who failed a previous line of therapy, with a higher rate of side effects and a lower rate of virologic response in patients who qualified as null responders to IFN based therapy. Clinical trials with triple therapy are ongoing in HCV-HIV coinfected patients. Furthermore, new IFN free regimen relying on the combination of direct acting antivirals are currently being evaluated in HCV genotype 1 and non-1 infected patients. These advances provide new hope in the management of chronic hepatitis C, including patients with hereditary bleeding disorders.

Treatment of human immunodeficiency virus and hepatitis B virus infections.

Whilst virally attenuated clotting factor concentrates are now safe with respect to transmission of HBV and HIV there are many individuals with haemophilia who were infected many years ago by these viruses. New combination therapies are available for treating both these virus infections and efficacy rates are increasing. Although many of the clinical studies are initially undertaken in non-haemophilia individuals, consideration needs to be given as to the possible benefits of including those with haemophilia in the clinical assessment.

Proficiency of transient elastography compared to liver biopsy for the assessment of fibrosis in HIV/HBV-coinfected patients.

Transient elastography (TE) is a noninvasive technique to evaluate liver fibrosis. We compared the performance of TE with liver biopsy (LB) in patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection. Patients prospectively underwent TE and LB. The diagnosis accuracy of TE was calculated using receiver operating characteristic (ROC) curves for different stages of fibrosis, and optimal cut-off values were defined. A sequential algorithm combining TE with biochemical score (Fibrotest) is proposed. Fifty-seven patients had both TE and LB (median time: 3 days) and two with proven cirrhosis, only TE. Forty-six (78%) were under antiretroviral therapy with anti-HBV drugs in 98%, and 19 (32%) had elevated alanine aminotransferase (ALT). A significant correlation was observed between liver stiffness measurement (LSM) and METAVIR fibrosis stages (P < 0.0001). Patients with elevated ALT tended to have higher LSM than those with normal ALT. The areas under the ROC curves were 0.85 for significant fibrosis (≥ F2), 0.92 for advanced fibrosis (≥ F3) and 0.96 for cirrhosis. Using a cut-off of 5.9 kPa for F ≥ 2 and 7.6 kPa for F ≥ 3, the diagnosis accuracy was 83% and 86%, respectively. With an algorithm combining TE and Fibrotest, 97% of patients were well classified for significant fibrosis. Using this algorithm, the need for LB can be reduced by 67%. In HIV/HBV-coinfected patients, most of them with normal ALT under antiretroviral treatment including HBV active drugs, TE was proficient in discriminating moderate to severe fibrosis from minimal liver disease.

A randomized trial of viral hepatitis prevention among underprivileged people in the Lyon area of France.

BACKGROUND: We compared the efficacy of two viral hepatitis B and C (VHBC) screening strategies, relative to no intervention, among underprivileged people (UP) living in shelters in the Lyon area. METHODS: Eighteen of 37 shelters were randomly sampled after stratification based on the accommodation capacity and the screening centres/shelters distance. Through randomization, the S0 strategy (no intervention), the S1 strategy [group information (GI) and referral for screening] and the S2 strategy (GI and in situ screening) were each applied in six shelters. A standardized questionnaire was offered to each participant. Follow-up of positive cases was organized via the reference centre of VHBC of Lyon. RESULTS: The screening completion rate (SCR) among 1276 included subjects in S0, S1 and S2 was 1.5, 42.8 and 59.7%, respectively (P < 10(-6)). This rate was higher in S2 regardless of the sociodemographic variable considered. Odds ratios (OR) of screening completion (SC) was significantly higher in S1 versus S0, OR = 49.8 [95% confidence interval (CI): 26.1-102.1], in S2 versus S0, OR = 98.5 (95% CI: 51.9-200.8) and in S2 versus S1, OR = 2.0 (95% CI: 1.3-2.9). Age, country of birth and professional inactivity were independently associated with SC. CONCLUSIONS: Health authorities must ensure widespread screening of UP, which is more effective when conducted in shelters than in screening centres.

Discordance between biochemical markers of liver activity and fibrosis (Actitest-Fibrotest) and liver biopsy in patients with chronic hepatitis C.

INTRODUCTION: The purpose of this clinical trial was to determine in routine practice and in comparison with liver biopsy the limitations of two blood tests, Actitest and Fibrotest, for the evaluation of hepatic activity and fibrosis in patients with chronic hepatitis C. METHODS: Routine blood tests, Actitest and Fibrotest, and liver biopsy were performed in 96 patients with chronic hepatitis C attending routine outpatient clinics. Receiver operating characteristics (ROC) curves were used to assess the diagnostic value of the biochemical tests in comparison with the METAVIR classification. RESULTS: The study population was predominantly male (63.5%) with a mean age of 48 years; 83.3% of the patients had genotype 1 hepatitis C virus infection. Treatment status was naive (62.5%), nonresponders (17.7%), relapsers (7.3%), or unknown (12.5%). The comparison of F0-F2 versus F3-F4 estimated the negative predictive value at 92% and the positive predictive value at 52% for a cut-off of 0.455. Discrepancies in activity score were more frequently due to a higher score of the biochemical test compared to biopsy (18 cases out of 19). Discrepancies for fibrosis were observed in 18 patients with a higher score for biochemical test in eight and a higher score for liver biopsy in 10 cases. A significant increase of gamma-glutamyl-transferase (GGT) (p=0.0001) and alanine aminotransferase (ALT) (p<0.0001) was observed in case of biochemical test overestimation of activity, and a significant increase of alpha2-macroglobulin (p=0.006) and GGT (p=0.018) in case of biochemical test overestimation of fibrosis. CONCLUSION: This prospective study confirms the good diagnostic value of biochemical tests for necrotico-inflammatory activity and fibrosis as compared with the histological analysis of liver biopsy. Clinicians must interpret Actitest and Fibrotest results with caution in patients with a significant elevation of ALT, and/or GGT and/or alpha2-macroglobulin which could overestimate hepatic injury.

Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection.

Hepatitis C virus genotype 4 (HCV-4) infection is progressing in Europe, where epidemiology and sustained virological response (SVR) seem to be different than in the Middle East. We analysed epidemiological features and SVR rates in a retrospective study of 1532 HCV-4-infected patients, including 1056 patients infected in France, 227 immigrants infected in Egypt and 249 in sub-Saharan Africa. SVR rates were assessed in 242 naive patients of the 1532, who received peginterferon plus ribavirin for 48 weeks. HCV subtype 4a or 4d was the most common among patients infected in France, where the predominant route of transmission was intravenous drug abuse. The 4a subtype was largely predominant (93%) among patients infected in Egypt, where transmission was mostly because of parenteral treatment for schistosomiasis. More than seven different subtypes and no predominant route of infection were found in patients infected in sub-Saharan Africa. Liver fibrosis was significantly less severe in patients infected in France and Africa than in patients infected in Egypt. SVR rates were higher in patients infected in Egypt, compared with those infected in France or Africa (54.9%, 40.3% and 32.4%, respectively, P < 0.05). An overall better response was observed in patients infected with the 4a subtype. In multivariate analysis, two factors were associated independently with SVR: the Egyptian origin of transmission and the absence of severe fibrosis. In conclusion, the distribution of HCV-4 subtypes varies with the geographical origin of transmission and affects the SVR following antiviral treatment.

Etanercept treatment for three months is safe in patients with rheumatological manifestations associated with hepatitis C virus.

OBJECTIVE: The treatment of the rheumatological manifestations associated with hepatitis C virus (HCV) remains difficult. To examine the safety of anti-tumour necrosis factor-alpha treatment, nine patients having rheumatological manifestations associated with HCV were treated with etanercept 25 mg twice a week for 3 months. METHODS: Five patients had a positive viral load at study entry (Group I), four were negative (Group II). Clinical data recorded were: disease duration, painful and swollen joint count, patient global and physician global assessment, the number of 18 specified fibromyalgia tender points and the Health Assessment Questionnaire score. Laboratory studies included checking for the presence of cryoglobulinaemia and transaminase levels. Quantitative HCV viral RNA was performed by real-time polymerase chain reaction (PCR). RESULTS: At 3 months, no patient was found to have evidence of increased hepatic inflammation based on serial serum transaminase levels. In the five patients from Group I with detectable HCV RNA, no significant viral load increase was observed. No reactivation was observed in the four patients from Group II with undetectable HCV RNA. The effect on the clinical rheumatological manifestations was more heterogeneous but appears to be lower than that observed in rheumatoid arthritis. CONCLUSION: In this phase II open short-term study, etanercept appeared to be safe in patients with articular manifestations associated with HCV.

Screening campaign of hepatitis C among underprivileged people consulting in health centres of Lyon area, France.

BACKGROUND: A screening campaign for hepatitis C virus (HCV) infection was carried out in eight health centres of Lyon from June 2003 until March 2004. The population targeted for screening was underprivileged individuals without any social insurance, protected by Couverture Mutuelle Universelle or Aide Médicale Etat (AME), to estimate the prevalence of anti-HCV antibodies in this population and to identify associated risk factors. METHODS: After training in HCV infection and screening, 43 general practitioners participated in the campaign. Information about patient socio-demographics and risk factors was collected prior to proposing screening serology. Blood samples were often taken in health centres. Follow-up of positive cases was organised via the Reference Centre of HCV Infection in Lyon with possible specialised consultations in health centres. RESULTS: The average age of the 988 individuals in the campaign was 37 years; 51% were women; 54% had a foreign nationality; 21% lived in sheltered accommodation; 19% were lodged in third-party accommodation; 9% were homeless; and 57% possessed less than euro562 (Revenu Minimum d'Insertion level). Screening was not proposed to nine patients because of medico-psychological problems. The acceptance rate for screening was 98.8% (967/979), and testing was carried out on 97.6% of these subjects (944/967). The prevalence of anti-HCV antibodies in the sample was 4.7% (44/944) (95% CI = 3.4-6.2). Nearly 80% of positive cases were unknown prior to the campaign. Multivariate logistic regression modelling identified lifetime injection drug use [odds ratios (OR) = 15.99; P < 0.0001], lifetime medical care in a foreign country (OR = 4.46; P = 0.001), and wearing tattoos (OR = 2.75; P = 0.048) as significant risk factors for carrying anti-HCV antibodies. Characteristics independently associated with HCV seropositivity were age between 40 and 49 years, AME benefits, and no social insurance. CONCLUSION: Wide acceptance of screening, high prevalence of anti-HCV antibodies (much higher than in the French population in general), a high proportion of positive cases unknown beforehand, and satisfactory follow-up of seropositive patients are all factors which support the need for a screening campaign targeting HCV infection in underprivileged persons living in France.

Structure-activity relationships of HIV-1 integrase inhibitors--enzyme-ligand interactions.

HIV-1 integrase is an essential enzyme for retroviral replication. It is involved in the integration of HIV DNA into host chromosomal DNA and appears to have no functional equivalent in human cells. Therefore it is an attractive and rational target for selective anti-AIDS therapy. A great number of HIV-1 integrase inhibitors have been described in the last decade and numerous reviews have been published. The biochemical mechanism of HIV-1 DNA integration, the enzyme structure and the possible targets for drug intervention have been thoroughly analyzed. Structure-based drug design including both ligand-based (pharmacophore) and target-based (docking) methods has also been discussed. The recent report of the crystal structure of HIV-1 integrase core domain with an inhibitor has given a new boost leading in the last two years to the emergence of diketoacids (DKAs). To date, with the dicaffeoyltartaric acids they are the only two classes of molecules that meet the criteria necessary to be considered lead molecules in the search for clinically useful inhibitors of HIV-1 integrase. After a survey of the function and the structure of this enzyme and the different available assays for the identification of new IN inhibitors, structure-activity relationships of HIV-1 integrase inhibitors that are expected to interact with the active site (or in its vicinity) will be discussed with emphasis on their different proposed mechanisms of action.