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.

Psychiatric and substance use disorders in HIV/hepatitis C virus (HCV)-coinfected patients: does HCV clearance matter? [Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) HEPAVIH CO13 cohort].

OBJECTIVES: The objective of this nested study was to assess the prevalence of psychiatric disorders in a sample of HIV/hepatitis C virus (HCV)-coinfected patients according to their HCV status. METHODS: The nested cross-sectional study, untitled HEPAVIH-Psy survey, was performed in a subset of HIV/HCV-coinfected patients enrolled in the French Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) CO13 HEPAVIH cohort. Psychiatric disorders were screened for using the Mini International Neuropsychiatric Interview (MINI 5.0.0). RESULTS: Among the 286 patients enrolled in the study, 68 (24%) had never received HCV treatment, 87 (30%) were treatment nonresponders, 44 (15%) were currently being treated and 87 (30%) had a sustained virological response (SVR). Of the 286 patients enrolled, 121 patients (42%) screened positive for a psychiatric disorder other than suicidality and alcohol/drug abuse/dependence, 40 (14%) screened positive for alcohol abuse/dependence, 50 (18%) screened positive for drug abuse/dependence, 50 (17.5%) were receiving an antidepressant treatment and 69 (24%) were receiving an anxiolytic. Patients with an SVR did not significantly differ from the other groups in terms of psychiatric disorders. Patients receiving HCV treatment screened positive less often for an anxiety disorder. The highest rate of drug dependence/abuse was among HCV treatment-naïve patients. CONCLUSIONS: Psychiatric disorders were frequent in HIV/HCV-coinfected patients and their rates were comparable between groups, even for patients achieving an SVR. Our results emphasize the need for continuous assessment and care of coinfected patients, even after HCV clearance. Drug addiction remains an obstacle to access to HCV treatment. Despite the recent advent and continued development of directly acting antiviral agents (DAAs), it is still crucial to offer screening and comprehensive care for psychiatric and addictive disorders.

Patterns of adherence to antiretroviral therapy and HIV drug resistance over time in the Stratall ANRS 12110/ESTHER trial in Cameroon.

OBJECTIVES: The emergence of HIV drug resistance is a crucial issue in Africa, where second-line antiretroviral therapy (ART) is limited, expensive and complex. We assessed the association between adherence patterns and resistance emergence over time, using an adherence measure that distinguishes low adherence from treatment interruptions, in rural Cameroon. METHODS: We performed a cohort study among patients receiving nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART in nine district hospitals, using data from the Stratall trial (2006-2010). Genotypic mutations associated with antiretroviral drug resistance were assessed when 6-monthly HIV viral loads were > 5000 HIV-1 RNA copies/mL. ART adherence data were collected using face-to-face questionnaires. Combined indicators of early (1-3 months) and late (6 months to t - 1; t is the time point when the resistance had been detected) adherence were constructed. Multivariate logistic regression and Cox models were used to assess the association between adherence patterns and early (at 6 months) and late (after 6 months) resistance emergence, respectively. RESULTS: Among 456 participants (71% women; median age 37 years), 45 developed HIV drug resistance (18 early and 27 late). Early low adherence (< 80%) and treatment interruptions (> 2 days) were associated with early resistance [adjusted odds ratio (95% confidence interval) 8.51 (1.30-55.61) and 5.25 (1.45-18.95), respectively]. Early treatment interruptions were also associated with late resistance [adjusted hazard ratio (95% confidence interval) 3.72 (1.27-10.92)]. CONCLUSIONS: The emergence of HIV drug resistance on first-line NNRTI-based regimens was associated with different patterns of adherence over time. Ensuring optimal early adherence through specific interventions, adequate management of drug stocks, and viral load monitoring is a clinical and public health priority in Africa.

Impact of drug consumption rooms on non-fatal overdoses, abscesses and emergency department visits in people who inject drugs in France: results from the COSINUS cohort.

BACKGROUND: The effectiveness of drug consumption rooms (DCRs) for people who inject drugs (PWID) has been demonstrated for HIV and hepatitis C virus risk practices, and access to care for substance use disorders. However, data on other health-related complications are scarce. Using data from the French COSINUS cohort, we investigated the impact of DCR exposure on non-fatal overdoses, abscesses and emergency department (ED) visits, all in the previous 6 months. METHODS: COSINUS is a 12-month prospective cohort study of 665 PWID in France studying DCR effectiveness on health. We collected data from face-to-face interviews at enrolment, and at 6 and 12 months of follow-up. After adjusting for other correlates (P-value < 0.05), the impact of DCR exposure on each outcome was assessed using a two-step Heckman mixed-effects probit model, allowing us to adjust for potential non-randomization bias due to differences between DCR-exposed and DCR-unexposed participants, while taking into account the correlation between repeated measures. RESULTS: At enrolment, 21%, 6% and 38% of the 665 participants reported overdoses, abscesses and ED visits, respectively. Multivariable models found that DCR-exposed participants were less likely to report overdoses [adjusted coefficient (95% CI): -0.47 (-0.88; -0.07), P = 0.023], abscesses [-0.74 (-1.11; -0.37), P < 0.001] and ED visits [-0.74 (-1.27; -0.20), P = 0.007]. CONCLUSION: This is the first study to show the positive impact of DCR exposure on abscesses and ED visits, and confirms DCR effectiveness in reducing overdoses, when adjusting for potential non-randomization bias. Our findings strengthen the argument to expand DCR implementation to improve PWID injection environment and health.

Adjuvant endocrine therapy with tamoxifen in young women with breast cancer: determinants of interruptions vary over time.

BACKGROUND: In premenopausal women with hormone receptor-positive breast cancer (BC), 5 years of tamoxifen is recommended. Little is known about reasons for interruption in this population. The aim was to estimate the incidence of tamoxifen interruption and its correlates among younger women. PATIENTS AND METHODS: Using a prospective cohort Elippse 40 of women with BC aged ≤ 40 diagnosed between 2005 and 2008, we studied 196 women. Tamoxifen interruption was defined as two or more consecutive months without dispensed prescription of tamoxifen, based on pharmacy refill database. Two periods were studied: between tamoxifen initiation and 16 months after BC diagnosis, and between 16 and 28 months. RESULTS: Among women treated with tamoxifen, 42% interrupted within the first 2 years of treatment. During the first period, treatment interruptions were associated with a lack of understandable information about endocrine treatment and insufficient social support. During the second period, another set of factors were associated with interruption: treatment side-effects, no longer fearing cancer relapse, lack of social support, no opportunity to ask questions at the time of diagnosis, and fewer treatment modalities. CONCLUSIONS: Improving information and patient-provider relationship might prevent interruption. Particular attention should be paid to women with little social support.

Role of treatment for depressive symptoms in relieving the impact of fatigue in HIV-HCV co-infected patients: ANRS Co13 Hepavih, France, 2006-2008.

Fatigue is a major component of quality of life (QOL) and is associated with depression in HIV-HCV co-infected individuals. We investigated whether treating depressive symptoms (DS) could mitigate the impact of fatigue on daily functioning in co-infected patients, even those at an advanced stage of disease. The analysis was conducted on enrollment data of 328 HIV-HCV co-infected patients recruited in the French nationwide ANRS CO 13 HEPAVIH cohort. Data collection was based on medical records and self-administered questionnaires which included items on socio-behavioural data, the fatigue impact scale (FIS) in three domains (cognitive, physical and social functioning), depressive symptoms (CES-D classification) and use of treatments for depressive symptoms (TDS). After multiple adjustment for gender and unemployment, CD4 cell count <200 per mm(3) was associated with a negative impact of fatigue on the physical functioning dimension (P = 0.002). A higher number of symptoms causing discomfort significantly predicted a higher impact of fatigue on all three dimensions (P < 0.001). This was also true for patients with DS receiving TDS when compared with those with no DS but receiving TDS. A significant decreasing linear trend (P < 0.001) of the impact of fatigue was found across the categories 'DS/TDS', 'DS/no TDS', 'no DS/TDS' and 'no DS/no TDS'. Despite limitations related to the cross-sectional nature of this study, our results suggest that routine screening and treatment for DS can reduce the impact of fatigue on the daily functioning of HIV-HCV co-infected patients and relieve the burden of their dual infection.

Factors Associated with HIV Status Disclosure in HIV-Infected Sub-Saharan Migrants Living in France and Successfully Treated with Antiretroviral Therapy: Results from the ANRS-VIHVO Study.

To estimate rates and identify correlates of HIV disclosure in migrants from sub-Saharan Africa (SSA) successfully treated, a sub-analysis was conducted in HIV-1 native SSA migrants, living in France with undetectable viral load on antiretroviral, included in the VIHVO adherence study. Logistic regression models assessed factors associated with HIV disclosure. Among 246 individuals (40 % male, median age 41), 79 % of those in a steady heterosexual partnership (n = 167) had disclosed their status to their partner, 55 % of the total 246 to a relative, and 33 % to (an)other person(s). Disclosure to one's steady partner was associated with a follow-up duration since HIV diagnosis of more than 5 years, a higher literacy level, a better social context and marital status. Women were more likely to disclose their HIV status to relatives. Interventions targeting this population should be provided to improve disclosure which in turn ensures better social support, testing of the partner and lower rates of undiagnosed HIV.

Immunosuppression and cancer: A comparison of risks in recipients of organ transplants and in HIV-positive individuals.

The comparison of cancers occurring excessively among HIV-infected and transplanted individuals may help to elucidate the relationship between immune surveillance, viral infections, and cancer. A longitudinal study was conducted on 2002 HIV-infected Italian subjects, 6072 HIV-infected French individuals, and 2878 Italian recipients of solid organ transplants. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were computed to quantify the risk for cancer, compared with the French and Italian general populations. The SIRs for all cancers were 9.8 (95% CI: 9.0-10.6) for HIV-infected individuals versus 2.2 (95% CI: 1.9-2.5) for transplant recipients. In both groups, most of the excess risk was attributable to virus-related cancers, such as Kaposi's sarcoma (KS; SIR = 451 in HIV-positive individuals, 125 in transplant recipients), non-Hodgkin's lymphoma (NHL; SIR = 62.1 and 11.1, respectively), and liver cancer (SIR = 9.4 and 4.1, respectively). Significantly increased SIRs for anal cancer and Hodgkin's lymphoma were found only among HIV-positive individuals. Among women younger than 40 years of age, a more than 10-fold increase in cervical cancer risk was found in both groups. Among HIV-infected individuals treatment with highly active antiretroviral therapies drastically reduced SIRs for KS and NHL only. These results show that HIV-infected individuals and transplant recipients share a similar pattern of cancer risk, largely due to virus-related cancers.

[Health related quality of life among HIV-HCV co-infected patients]. / La qualité de vie des patients co-infectés par le VIH et le VHC.

BACKGROUND: To assess factors associated with higher levels of health-related quality-of-life among HIV-HCV co-infected injecting drug users and more specifically, to explore the role of injecting drug status and drug maintenance treatment on health-related quality-of-life. METHODS: The two hundred and forty participants were patients enrolled in the MANIF cohort of HIV-HCV patients infected through injecting drug use who completed a self-administered questionnaire that included a health-related quality-of-life evaluation at the 42 month follow-up. A self-administered questionnaire collected information about socio-demographic characteristics, health-related quality-of-life (as measured by SF-12), injecting drug status and drug maintenance treatment, depressive symptoms, self-reported symptoms related to HIV treatment; clinical characteristics were obtained from medical records. RESULTS: Higher levels of both mental and physical health-related quality-of-life were found in patients with no depressive symptoms, abstinent from drugs and experiencing few drug related problems. Patients on drug maintenance treatment who stopped injecting drugs had better mental health-related quality-of-life than injectors but lower levels of mental health-related quality-of-life than abstinent patients. Mental health-related quality-of-life was also independently higher in patients receiving high social support. Physical health-related quality-of-life was independently higher for patients who stopped injection, whether on drug maintenance treatment or not, for patients on anti-retroviral treatment and for patients who remained in clinical stage A. CONCLUSIONS: Drug maintenance treatment seems to be associated with higher health-related quality-of-life among patients HIV-HCV co-infected by drug use, but it is still necessary to help patients cope with the mental impact of drug cessation. These results underline the need to provide regular psychological support and counselling for HIV-HCV co-infected injecting drug users during the medical follow-up for HIV-disease.

Adherence to HAART in French HIV-infected injecting drug users: the contribution of buprenorphine drug maintenance treatment. The Manif 2000 study group.

OBJECTIVES: To assess adherence to highly active antiretroviral therapies (HAART) in a cohort of French patients infected by HIV through injection drug use (IDU), and the impact on adherence of buprenorphine ambulatory drug maintenance treatment (DMT) which has been widely introduced since 1996. DESIGN: Adherence assessment at first visit after initiation of HAART in the MANIF2000 cohort study. METHODS: Patient's face-to-face and self-administered questionnaires. Univariate and logistic regression adjusted odds ratios (OR) to compare characteristics of non-adherent versus adherent patients. RESULTS: Of the 164 patients, 34.8% took less than 80% of the prescribed HAART doses during the previous week. Decrease in viral load titres after initiation of HAART was significantly lower among non-adherent patients. After adjustment by logistic regression, non-adherence was associated with younger age, alcohol consumption, frequency of negative life-events during the prior 6 months and active drug use. However, IDU in buprenorphine DMT reached higher levels of adherence (78.1%) than ex-IDU (65.5%), although this difference did not reach statistical significance. CONCLUSION: Prescription of buprenorphine DMT may increase adherence to HAART among HIV-infected opiate-dependent patients. Reducing the negative impact of stressful life-events through psychosocial interventions should be considered, even for those who have stopped using drugs.

The effect of cataract severity and morphology on the reliability of the Lens Opacities Classification System II (LOCS II).

Data collected from 3646 eyes in the Italian-American Natural History Study of Age-Related Cataract were used to investigate whether the reliability of the Lens Opacities Classification System II (LOCS II) by the severity of the opacity that is being graded or is influenced by the presence and severity of coexisting opacities. Reliability was assessed by comparing the slit-lamp gradings of two clinical examiners (346 eyes) and the gradings performed at the slit lamp with gradings of photographs (3646 eyes). The severity of cortical and nuclear opacities did not affect the reproducibility of slit-lamp gradings, but clinical grading of posterior subcapsular opacities became more reliable as the severity of the posterior subcapsular opacities increased. More advanced coexisting opacities decreased the agreement in the slit-lamp diagnosis of nuclear, but not cortical or posterior subcapsular, opacities. Comparisons of clinical and photographic gradings showed very good to excellent agreement for nuclear and cortical opacities, regardless of the severity of the specific opacity or the severity of the coexisting opacities. Agreement in diagnosing posterior subcapsular opacities was decreased in eyes with milder posterior subcapsular opacities and in eyes with more severe coexisting nuclear and/or cortical opacities. The effect of the severity of the opacity being graded and the severity of coexisting opacities on the reliability of the LOCS II must be considered in studies that use the system to classify and grade cataracts.

A case-control study on risk factors for Peyronie's disease.

The aim of this study was to investigate the relationship between history of selected diseases, genital traumas, and Peyronie's disease. A hospital-based case-control study was conducted at the Andrologic and Surgical Outpatient Units of the Policlinico Gemelli, Rome, where 134 men with Peyronie's disease and 134 male controls were interviewed. The association between Peyronie's disease and selected characteristics was estimated by means of odds ratios (OR) and 95% confidence intervals (CI). Patients who underwent invasive procedures on the penis (i.e., urethral catheterization, cystoscopy, and transurethral prostatectomy) had a 16-fold increased risk for Peyronie's disease (OR = 16.1, 95% CI: 1.8-142), while a nearly three-fold increase was observed among patients who had genital and/or perineal traumatisms (95% CI: 1.0-7.1). A history of urethritis, uricacidemia, and lipoma was also significantly associated with an increased risk for Peyronie's disease. Twenty-one percent of the cases and none of the controls were affected by Dupuytren's contracture, and 4% of cases and none of the controls reported familial history for Peyronie's disease. The frequency of inflammatory or fibromatous lesions of the genital tract of the partner was significantly higher in men with Peyronie's disease than among controls. These results were consistent when performing a stratified analysis according to the type of controls (i.e., controls affected by urologic or by digestive conditions) to rule out the potential effect of recall bias. The findings of the study lend support to clinical reports stressing the importance of genital traumatisms and genetic conditions in the development of Peyronie's disease.

Access to antiretroviral treatment among French HIV infected injection drug users: the influence of continued drug use. MANIF 2000 Study Group.

STUDY OBJECTIVE: To determine the influence of continued drug use and its perception by prescribing physicians on access to antiretroviral treatment among French HIV infected injection drug users (IDUs). DESIGN: Cross sectional including enrollment data (October 1995-1996) of the cohort study MANIF 2000. Access to treatment is compared in three groups: former IDUs (n = 68) and active IDUs whether or not this behaviour remains undetected (n = 38) or detected (n = 17) by physicians. SETTING: Hospital departments for specialist AIDS care in south eastern France and inner suburbs of Paris. PATIENTS: All enrolled patients with CD4+ cell counts < 400 with detailed clinical history, access to treatment, risk behaviours, and past drug use as reported by both physicians and patients (n = 123). MAIN RESULTS: A minority (43.9%) already received an antiretroviral treatment. Active IDUs had worst socioeconomic and psychological conditions but only those detected by physicians were considered as poorly compliant. Logistic regression showed that, with respect to ex-IDUs and independently of clinical stage, active IDUs, whether or not they were perceived as such by physicians, were threefold more likely not to receive antiretroviral treatment. CONCLUSIONS: Even among French HIV infected IDUs who have regular access to AIDS specialised hospital care, continued drug use reduced the likelihood of being prescribed antiretroviral treatment. To reduce delays in access to new treatments, specific efforts must be devoted towards both AIDS specialists and IDU patients to overcome current stereotypes of non-compliance associated with continued injection.

Use of buprenorphine in HIV-infected injection drug users: negligible impact on virologic response to HAART. The Manif-2000 Study Group.

Some HIV-infected injecting drug users (IDUs) on drug abuse maintenance treatment have access to highly active antiretroviral therapy (HAART); this raises questions about the effects of individual treatments on the efficacy of HAART. The French Cohort Study of HIV-infected IDUs - MANIF-2000 - allowed one to assess whether buprenorphine differentially impacts efficacy of HAART. Of the 103 HAART-treated patients, (excluding active IDUs and patients on methadone), 20 were on buprenorphine substitution treatment and 83 were ex-IDUs. A linear regression model used the differences in viral load titre before and after treatment initiation, as a dependent variable, and showed that buprenorphine treatment was not significantly associated with viral load trend. This was also the case when adjusting for other potential confounders, and suggests that there is no major short-term influence of buprenorphine on HIV viral load in HAART-treated patients.

Does snatching frequency really indicate food ingestion in the Nile tilapia?

The fitness of the snatching frequency as an indicator of food intake in Nile tilapia fingerlings, Oreochromis niloticus (L), was studied. Five groups of four individuals each were used after a two-day starvation period. The hierarchical rank among individuals in the same group was registered. Food in the form of tiny pellets (ranging from 1.30 to 1.95 mm in diameter) was offered, and the individual snatching frequency was observed during a 20-min period. The animals were then sacrificed for evaluation of stomach contents. It was concluded that snatching frequency is not a good parameter to indicate individual food intake in this species when fed as a group with pellets crushed into tiny particles. This raises a problem for investigations that require evaluation of the cumulative effect of competition on food intake, such as growth or conversion efficiency studies. Furthermore, a very low correlation between snatching frequency and food intake was shown in the third hierarchical rank. It is suggested that the linearity assumed in such hierarchies should be reconsidered.

Prenatal and perinatal determinants of neonatal seizures occurring in the first week of life.

To evaluate prenatal and perinatal risk factors for early neonatal seizures, we conducted a case-control study including 100 newborns with neonatal seizures in the first week of life and 204 controls randomly selected from a list of healthy newborns born in the same hospital during the study period. Generalized tonic seizures were the most common seizures observed (29%), although the majority of newborns (71%) experienced more than one type of seizure. The most frequent presumed etiology of neonatal seizures was hypoxic-ischemic encephalopathy (30%). A history of epilepsy in first-degree relatives was found only for cases. Neonatal seizures were found to be associated with maternal disease in the 2 years before pregnancy, mother's weight gain > 14 kg during pregnancy, placental pathology, preeclampsia, low birthweight, low gestational age, and jaundice in the first 3 days of life. The need for cardiopulmonary resuscitation was found only for cases (37%). The causal pathways for neonatal seizures often begin before birth, and some of the factors identified may be preventable.

HIV screening for pregnant women in south eastern France: evolution 1992-1994-1996.

OBJECTIVES: To assess the evolution of the HIV screening practices towards pregnant women between 1992 and 1996, in relation with the 1993 French mandatory obligation to offer prenatal HIV testing and recent therapeutic possibilities to reduce HIV vertical transmission. STUDY DESIGN: Three successive surveys (January 1992, May 1994 and May 1996) about HIV screening policies among medical chiefs of all prenatal care and abortion departments of South Eastern France. Sixty-seven of the 74 departments concerned agreed to participate in the three surveys. RESULTS: The proportion of departments practising routine prenatal HIV screening had not increased since 1992 (89%) but systematic women's consent is more often requested (65.5 vs. 38.2%, P < 0.01). In the context of abortion, HIV testing is more often routinely offered (38.1 vs. 16.4%, P < 0.05) but selective screening remains a frequent practice (29.1%). CONCLUSION: Mandatory proposal of HIV testing to women who terminate could improve access to test but is not sufficient to guarantee adequate preventive counselling.