Assessing Molecular Point-of-Care Testing and Dried Blood Spot for Hepatitis C Virus Screening in People Who Inject Drugs.

BACKGROUND: Injecting drug use is a major driver of hepatitis C virus (HCV) spread worldwide, and the World Health Organization (WHO) has identified people who inject drugs (PWID) as a key population to target for HCV screening and care. Point-of-care (POC) hepatitis C tests and dried blood spot (DBS) sampling offer benefits for the management of patients with HCV infection by increasing HCV testing and linkage to care in different nonclinical settings. The aims of this prospective study were to evaluate the feasibility and the acceptability of use HCV ribonucleic acid (RNA) POC and fingerstick DBS testing in social-medical risk-reduction centers and to describe the cascade of care among PWID in France. METHODS: Between June 2018 and February 2019, 89 consecutive HCV-seropositive PWID attending 2 drug treatment services and 1 supervised consumption room in inner Paris were invited to participate in further evaluation, undergoing a clinical review with a liver assessment and blood tests including fingerstick capillary whole blood POC HCV RNA testing and fingerstick DBS sampling. RESULTS: Of the 89 participants enrolled, HCV RNA was detected in 34 (38.6%) participants. Fingerstick whole blood POC RNA testing and HCV RNA detection from DBS sample were feasible and acceptable among PWID with no major difference in terms of HCV RNA detection rate. Overall, 16 participants received pan-genotypic antiviral treatment. The proportion of PWID with sustained virologic response at 12 weeks was 81.2%, with data for 3 patients still pending. CONCLUSIONS: One-step screening strategy based on the detection of HCV RNA would engage people in care for treatment scale-up and HCV elimination.

Increased liver stiffness is associated with mortality in HIV/HCV coinfected subjects: The French nationwide ANRS CO13 HEPAVIH cohort study.

BACKGROUND: The association between liver stiffness measurements (LSM) and mortality has not been fully described. In particular the effect of LSM on all-cause mortality taking sustained virological response (SVR) into account needs further study. METHODS: HIV/HCV participants in the French nation-wide, prospective, multicenter ANRS CO13 HEPAVIH cohort, with ≥1 LSM by FibroScan (FS) and a detectable HCV RNA when the first valid FS was performed were included. Cox proportional hazards models with delayed entry were performed to determine factors associated with all-cause mortality. LSM and SVR were considered as time dependent covariates. RESULTS: 1,062 patients were included from 2005 to 2015 (69.8% men, median age 45.7 years (IQR 42.4-49.1)). 21.7% had baseline LSM >12.5 kPa. Median follow-up was 4.9 years (IQR 3.2-6.1). 727 (68.5%) were ever treated for HCV: 189 of them (26.0%) achieved SVR. 76 deaths were observed (26 liver-related, 10 HIV-related, 29 non-liver-non-HIV-related, 11 of unknown cause). At the age of 50, the mortality rate was 4.5% for patients with LSM ≤12.5 kPa and 10.8% for patients with LSM >12.5 kPa. LSM >12.5 kPa (adjusted Hazard Ratio [aHR] = 3.35 [2.06; 5.45], p<0.0001), history of HCV treatment (aHR = 0.53 [0.32; 0.90], p = 0.01) and smoking (past (aHR = 5.69 [1.56; 20.78]) and current (3.22 [0.93; 11.09]) versus never, p = 0.01) were associated with all-cause mortality independently of SVR, age, sex, alcohol use and metabolic disorders. CONCLUSION: Any LSM >12.5 kPa was strongly associated with all-cause mortality independently of SVR and other important covariates. Our results suggest that close follow-up of these patients should remain a priority even after achieving SVR.

Factors associated with non-AIDS-defining cancers and non HCV-liver related cancers in HIV/HCV-coinfected patients- ANRS-CO13 HEPAVIH cohort.

Compared to the general population, HIV-infected patients are at higher risk of developing non-AIDS-defining cancers. Chronic HCV infection has also been associated with a higher risk than that of the general population of developing cancers other than hepatocarcinoma. Evaluation of the impact of HCV-related factors on non-AIDS-defining and non HCV-liver (NANL) related cancers among HIV/HCV co-infected patients are scarce. The aim of this study was to identify the impact of HIV/HCV clinical characteristics on NANL related cancers in a large cohort of HIV/HCV-coinfected patients followed from 2005 to 2017. Cox proportional hazards models with delayed entry were used to estimate factors associated with NANL related cancer. Among 1391 patients followed for a median of 5 years, 60 patients developed NANL related cancers, yielding an incidence rate of 8.9 per 1000 person-years (95% CI, [6.6-11.1]). By final multivariable analysis, after adjustment for sex, tobacco or alcohol consumption, baseline CD4 cell count and HCV sustained viral response (SVR), age and a longer duration since HIV diagnosis were independently associated with a higher risk of NANL related cancer (aHR for each additional year 1.10, 95% CI 1.06-1.14, p<0.0001 and 1.06, 95% CI 1.01-1.11, p = 0.02, respectively). Duration of HCV infection, cirrhosis, HCV viral load, genotype and SVR were not associated with the occurrence of NANL related cancer. Among HIV/HCV-coinfected patients, age and the duration of HIV infection were the only characteristics found to be associated with the occurrence of NANL related cancer. In contrast, no association was observed with any HCV-related variables.

Evolution of patients' socio-behavioral characteristics in the context of DAA: Results from the French ANRS CO13 HEPAVIH cohort of HIV-HCV co-infected patients.

BACKGROUND: Direct-acting antivirals (DAA) have dramatically increased HCV cure rates with minimal toxicity in HIV-HCV co-infected patients. This study aimed to compare the socio-behavioral characteristics of patients initiating pegylated-interferon (PEG-IFN)-based HCV treatment with those of patients initiating DAA-based treatment. METHODS: ANRS CO13 HEPAVIH is a national multicenter prospective cohort started in 2005, which enrolled 1,859 HIV-HCV co-infected patients followed up in French hospital outpatient units. Both clinical/biological and socio-behavioral data were collected during follow-up. We selected patients with socio-behavioral data available before HCV treatment initiation. RESULTS: A total of 580 patients were included in this analysis. Of these, 347 initiated PEG-IFN-based treatment, and 233 DAA-based treatment. There were significant differences regarding patient mean age (45 years±6 for the PEG-IFN group vs. 52 years±8 for the DAA group, p<0.001), unstable housing (21.4% vs. 11.2%, p = 0.0016), drug use (44.7% vs. 29.6%, p = 0.0003), regular or daily use of cannabis (24.3% vs. 15.6%, p = 0.0002), a history of drug injection (68.9% vs 39.0%, p<0.0001) and significant liver fibrosis (62.4% vs 72.3%, p = 0.0293). In multivariable analysis, patients initiating DAA-based treatment were older than their PEG-IFN-based treatment counterparts (aOR = 1.17; 95%CI [1.13; 1.22]). Patients receiving DAA treatment were less likely to report unstable housing (0.46 [0.24; 0.88]), cannabis use (regular or daily use:0.50 [0.28; 0.91]; non-regular use: 0.41 [0.22; 0.77]), and a history of drug injection (0.19 [0.12; 0.31]). CONCLUSION: It is possible that a majority of patients who had socio-economic problems and/or a history of drug injection and/or a non-advanced disease stage were already treated for HCV in the PEG-IFN era. Today, patients with unstable housing conditions are prescribed DAA less frequently than other populations. As HCV treatment is prevention, improving access to DAA remains a major clinical and public health strategy, in particular for individuals with high-risk behaviors.

Significant reductions in alcohol use after hepatitis C treatment: results from the ANRS CO13-HEPAVIH cohort.

BACKGROUND AND AIMS: Few data exist on changes to substance use patterns before and after hepatitis C virus (HCV) treatment. We used longitudinal data of HIV-HCV co-infected individuals to examine whether receiving pegylated interferon (Peg-IFN)-based therapy irrespective of HCV clearance could modify tobacco, cannabis and alcohol use. DESIGN: A prospective cohort of HIV-HCV co-infected individuals was enrolled from 2006. Participants' clinical data were retrieved from medical records and socio-demographic and behavioural characteristics were collected by yearly self-administered questionnaires. SETTING: Data were collected across 17 hospitals in France. PARTICIPANTS: All HIV-HCV co-infected patients who initiated HCV treatment during follow-up and answered items regarding substance use in at least one yearly questionnaire (258 patients, 671 visits). INTERVENTION: HCV treatment consisted of Peg-IFN-based regimens. MEASUREMENTS: Four time-varying outcomes: hazardous alcohol use (Alcohol Use Disorders Identification Test-C > 3/4 for women/men), number of alcohol units/month, binge drinking, cannabis and tobacco use. Mixed models assessed the effect of HCV treatment status (not yet treated, treated and HCV-cleared, treated and HCV-chronic) on each outcome. FINDINGS: A significant decrease (more than 60% reduction) in both hazardous alcohol use and binge drinking and a reduction of 10 alcohol units/month was observed after HCV treatment (irrespective of HCV clearance). No significant effect of HCV treatment status was found on tobacco use and regular cannabis use, but HCV 'clearers' reported less non-regular use of cannabis. CONCLUSIONS: Hepatitis C virus (HCV) treatment appears to help HIV-HCV co-infected patients reduce alcohol use.

Real-World Efficacy of Daclatasvir and Sofosbuvir, With and Without Ribavirin, in HIV/HCV Coinfected Patients With Advanced Liver Disease in a French Early Access Cohort.

BACKGROUND: Efficacious, well-tolerated, direct antiviral agents have drastically changed the prognosis of hepatitis C virus (HCV) disease, but real-world data for oral treatments are limited in key populations such as HIV/HCV coinfection with advanced liver disease. Daclatasvir (DCV) efficacy and safety was assessed in the French "Autorisation Temporaire d'Utilisation" (ATU) program, providing DCV ahead of market authorization to patients with advanced HCV disease without other treatment options. METHODS: This was a subanalysis of HIV/HCV coinfected ATU patients treated with DCV plus sofosbuvir (SOF). Recommended duration was 24 weeks; addition of ribavirin (RBV) and/or shorter treatment was at the physician's discretion. The primary efficacy analysis was sustained virologic response at posttreatment week 12 (SVR12; modified intention-to-treat). Safety was assessed by spontaneous adverse event reporting. RESULTS: The efficacy population (N = 407) was mostly cirrhotic (72%, of whom 18% were decompensated), HCV treatment-experienced (82%), and infected with genotypes 1 (69%), 3 (12%), or 4 (19%). Median CD4 was 555 cells/mm; 95% had HIV RNA <50 copies/mL. Most (74%) were treated for 24 weeks; 14% received RBV. SVR12 was 92% overall (95% confidence interval: 88.6% to 94.0%); 90% (86.4% to 93.2%) in patients with cirrhosis; 95% (88.9% to 97.5%) in patients without cirrhosis. SVR12 was consistent across HCV genotypes and antiretroviral regimens. Among 617 patients with safety data, 7 discontinued for an adverse event and 10 died. CONCLUSIONS: DCV+SOF±RBV achieved high SVR12 and was well tolerated in this large real-world cohort of HIV/HCV coinfected patients with advanced liver disease.

Efficacy and safety of direct-acting antiviral regimens in HIV/HCV-co-infected patients - French ANRS CO13 HEPAVIH cohort.

BACKGROUND & AIMS: There is little data available on the use of new oral direct-acting antiviral (DAA) regimens to treat human immunodeficiency virus and hepatitis C virus (HIV/HCV) co-infected patients in real-life settings. Here, the efficacy and safety of all-oral DAA-based regimens in HIV/HCV-co-infected patients enrolled in the French nationwide ANRS CO13 HEPAVIH observational cohort are reported. METHODS: HIV/HCV-co-infected patients enrolled in the ANRS CO13 HEPAVIH observational cohort were included if they began an all-oral DAA-based regimen before 1st May 2015 (12-week regimens) or 1st February 2015 (24-week regimens). Treatment success (SVR12) was defined by undetectable HCV-RNA 12weeks after treatment cessation. Exact logistic regression analysis was used to identify factors associated with SVR12. RESULTS: A total of 323 patients (74% men) with a median age of 53years were included, 99% of whom were on combination antiretroviral therapy (cART). HIV RNA load was <50 copies/ml in 88% of patients; median CD4 cell count was 540/mm3; 60% of patients were cirrhotic; 68% had previously received unsuccessful anti-HCV treatment. cART was protease inhibitor (PI)-based in 23%, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based in 15%, and integrase inhibitor (II)-based in 38%, while 24% of patients received other regimens. The SVR12 rate was 93.5% overall (95% confidence interval [CI]: 90.2-95.9), 93.3% (88.8-96.4) in patients with cirrhosis and 93.8% (88.1-97.3) in patients without cirrhosis. The SVR12 rates were 93.1% (84.5-97.7), 91.8% (80.4-97.7) and 95.8% (90.5-98.6) respectively, in patients receiving PI-based, NNRTI-based and II-based cART. In adjusted analysis, SVR12 was not associated with HIV RNA load, the cART regimen, cirrhosis, prior anti-HCV treatment, the duration of anti-HCV therapy, or ribavirin use. The most common adverse effects were fatigue and digestive disorders. CONCLUSIONS: New all-oral DAA regimens were well-tolerated and yielded high SVR12 rates in HIV/HCV-co-infected patients. LAY SUMMARY: We evaluated efficacy and safety of all-oral DAA regimens in a large French nationwide observational cohort study of HIV/HCV co-infected patients. Sustained virological response 12weeks after treatment cessation was 93.5% overall. The all-oral DAA regimens were well-tolerated and most common adverse effects were fatigue and digestive disorders.

All-oral Direct-acting Antiviral Regimens in HIV/Hepatitis C Virus-coinfected Patients With Cirrhosis Are Efficient and Safe: Real-life Results From the Prospective ANRS CO13-HEPAVIH Cohort.

BACKGROUND: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients with cirrhosis have long been considered to be difficult to treat, and real-life efficacy and tolerance data with all-oral direct-acting antiviral (DAA) combinations in these patients are scarce. METHODS: Cirrhotic HIV/HCV-coinfected patients enrolled in the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) CO13 HEPAVIH cohort initiating an all-oral DAA regimen were consecutively included. A negative HCV RNA result at 12 weeks of follow-up or thereafter was assumed as a sustained virologic response (SVR12). Adjusted exact logistic regression was used to study factors associated with treatment outcome. RESULTS: We included 189 patients who initiated an all-oral DAA regimen with the following characteristics: median age 53.2 years; 74.6% male; Centers for Disease Control and Prevention classification A/B/C: 37%/31%/32%; Child-Pugh class A/B/C: 91%/8%/1%; 87% with HIV RNA <50 copies/mL; 99% on antiretrovirals; median CD4 count: 489 cells/µL; HCV treatment naive 29%; HCV genotype 1/2/3/4: 58%/4%/17%/21%. Sofosbuvir (SOF) + daclatasvir ± ribavirin (RBV) was used in 123 patients, SOF + RBV in 30, SOF + simeprevir in 11, and SOF + ledipasvir in 23. An SVR12 was reported in 93.1% of the patients (95% confidence interval, 88.5%-96.3%). In adjusted analyses, no difference was found between 12 or 24 weeks of treatment, in patients receiving RBV or not, and in treatment-naive vs experienced patients. Premature stop of DAA was reported for 8 patients. One patient died during treatment (unknown cause), and 12 other patients developed liver-related events. CONCLUSIONS: In this prospective real-life cohort, all-oral DAA regimens were well tolerated and associated with a high virologic efficacy in cirrhotic HIV/HCV-coinfected patients. This should not alleviate the surveillance for liver-related events in these patients.

A new 3p25 locus is associated with liver fibrosis progression in human immunodeficiency virus/hepatitis C virus-coinfected patients.

There is growing evidence that human genetic variants contribute to liver fibrosis in subjects with hepatitis C virus (HCV) monoinfection, but this aspect has been little investigated in patients coinfected with HCV and human immunodeficiency virus (HIV). We performed the first genome-wide association study of liver fibrosis progression in patients coinfected with HCV and HIV, using the well-characterized French National Agency for Research on AIDS and Viral Hepatitis CO13 HEPAVIH cohort. Liver fibrosis was assessed by elastography (FibroScan), providing a quantitative fibrosis score. After quality control, a genome-wide association study was conducted on 289 Caucasian patients, for a total of 8,426,597 genotyped (Illumina Omni2.5 BeadChip) or reliably imputed single-nucleotide polymorphisms. Single-nucleotide polymorphisms with P values <10-6 were investigated in two independent replication cohorts of European patients infected with HCV alone. Two signals of genome-wide significance (P < 5 × 10-8 ) were obtained. The first, on chromosome 3p25 and corresponding to rs61183828 (P = 3.8 × 10-9 ), was replicated in the two independent cohorts of patients with HCV monoinfection. The cluster of single-nucleotide polymorphisms in linkage disequilibrium with rs61183828 was located close to two genes involved in mechanisms affecting both cell signaling and cell structure (CAV3) or HCV replication (RAD18). The second signal, obtained with rs11790131 (P = 9.3 × 10-9 ) on chromosome region 9p22, was not replicated. CONCLUSION: This genome-wide association study identified a new locus associated with liver fibrosis severity in patients with HIV/HCV coinfection, on chromosome 3p25, a finding that was replicated in patients with HCV monoinfection; these results provide new relevant hypotheses for the pathogenesis of liver fibrosis in patients with HIV/HCV coinfection that may help define new targets for drug development or new prognostic tests, to improve patient care. (Hepatology 2016;64:1462-1472).

High Proportion of HIV-HCV Coinfected Patients with Advanced Liver Fibrosis Requiring Hepatitis C Treatment in Haiphong, Northern Vietnam (ANRS 12262).

RATIONALE AND AIMS: Screening and treatment for chronic hepatitis C are very limited in Vietnam and clinical data on HCV-related liver disease in HIV-coinfected people are almost inexistent. This study aimed to assess the severity of liver fibrosis and its risk factors in HIV-HCV coinfected patients in Haiphong, Northern Vietnam. METHODS: A cross-sectional study was conducted at a HIV outpatient clinic. Consecutive HIV treated adults with positive HCV serology completed a standardised epidemiological questionnaire and had a comprehensive liver assessment including hepatic elastography (Fibroscan®, Echosens). RESULTS: From February to March 2014, 104 HIV-HCV coinfected patients receiving antiretroviral therapy (ART) were prospectively enrolled (99 males, median age: 35.8 (32.7-39.6) years, median CD4 count: 504 (361-624) /mm3. Of them, 93 (89.4%) had detectable HCV RNA (median 6.19 (4.95-6.83 Log10 IU/mL). Patients were mainly infected with genotypes 1a/1b (69%) and genotypes 6a/6e (26%). Forty-three patients (41.3%) had fibrosis ≥F2 including 24 patients (23.1%) with extensive fibrosis (F3) and/or cirrhosis (F4). In univariate analysis, excessive alcohol consumption, estimated time duration from HCV infection, nevirapine and lopinavir-based ARV regimen and CD4 nadir were associated factors of extensive fibrosis/cirrhosis. Alcohol abuse was the only independent factor of extensive fibrosis in multivariate analysis. Using Fibroscan® as a gold standard, the high thresholds of AST-to-platelet ratio index (APRI) and fibrosis-4 score (FIB-4) had very good performances for the diagnosis of extensive fibrosis/cirrhosis (Se: 90 and 100%, Sp:84 and 81%, AUROCs = 0.93, 95%CI: 0.86-0.99 and 0.96 (0.92-0.99), respectively). CONCLUSION: In this study, nearly 25% of HIV-HCV coinfected patients successfully treated with ART have extensive fibrosis or cirrhosis, and therefore require urgently HCV treatment.

Considerations for the long-term management of women living with HIV in Europe.

The average age at which women are first diagnosed with HIV is increasing and, due to advances in antiretroviral therapy (ART), women are living with HIV for longer. Once regarded as a fatal disease of young males, HIV is now considered a lifelong chronic condition affecting both men and women into older age. This raises questions for the long-term management of women living with HIV in Europe, such as how age affects the ART response, what the consequences are of long-term ART, and whether the comorbidities of ageing and menopause are different in women with HIV compared with men or uninfected women. Non-AIDS-related events, such as cancer, are increasingly responsible for the deaths of women with HIV, and European guidelines now recommend that they undergo regular screening for breast, cervical and colorectal cancer, and vaccination for human papillomavirus. The other major outcome of the greater life expectancy of women living with HIV is that a greater number are reaching menopause. Some studies suggest that HIV infection is linked with earlier onset of menopause and altered menopausal symptomatology. Many questions remain, and there is a need for more studies addressing ageing and sustained ART use in women living with HIV in Europe.

The need for data on women living with HIV in Europe.

Across Europe, women account for one-third of new diagnoses of HIV and yet data to guide the treatment of women living with HIV are limited, a situation largely due to under-representation of women in clinical trials. SHE is a European initiative co-led by a medical faculty of HIV physicians and a community peer-support faculty of women living with HIV, with the common goal of improving the outcomes and quality of life of women living with HIV.In 2011, two meetings of the SHE medical faculty and invited specialists in HIV medicine were convened to discuss the situation of and clinical care for women living with HIV in Europe. At the first meeting, available data on women living with HIV in Europe were reviewed and knowledge gaps were identified and prioritized. At the second meeting, delegates agreed upon next steps required to address the highest priority challenges. The most important requirements that were identified included additional, up-to-date guidance on clinical management of women (including pregnant women) living with HIV, greater coordination of European country registries of antiretroviral therapy in pregnant women, and generation of more gender-specific clinical data. The current article introduces the five key SHE topics pertaining to the care of women living with HIV in Europe as defined by the SHE faculty and summarizes the findings of the group in terms of data gaps. The remaining articles within this supplement review current data on the five SHE topics.

Self-reported alcohol abuse in HIV-HCV co-infected patients: a better predictor of HIV virological rebound than physician's perceptions (HEPAVIH ARNS CO13 cohort).

AIMS: Studying alcohol abuse impact, as measured by physicians' perceptions and patients' self-reports, on HIV virological rebound among patients chronically co-infected with HIV and hepatitis C virus (HCV). DESIGN: Cohort study. SETTING: Seventeen French hospitals. PARTICIPANTS: Five hundred and twelve patients receiving antiretroviral therapy (ART) with an undetectable initial HIV viral load and at least two viral load measures during follow-up. MEASUREMENTS: Medical records and self-administered questionnaires. HIV virological rebound defined as HIV viral load above the limit of detection of the given hospital's laboratory test. Alcohol abuse defined as reporting to have drunk regularly at least 4 (for men) or 3 (for women) alcohol units per day during the previous 6 months. Correlates of time to HIV virological rebound identified using Cox proportional hazards models. FINDINGS: At enrolment, 9% of patients reported alcohol abuse. Physicians considered 14.8% of all participants as alcohol abusers. Self-reported alcohol abuse was associated independently with HIV virological rebound [hazard ratio (95% confidence interval): 2.04 (1.13-3.67); P = 0.02], after adjustment for CD4 count, time since ART initiation and hospital HIV caseload. No significant relationship was observed between physician-reported alcohol abuse and virological rebound (P = 0.87). CONCLUSIONS: In France, the assessment of alcohol abuse in patients co-infected with HIV and hepatitis C virus should be based on patients' self-reports, rather than physicians' perceptions. Baseline screening of self-reported alcohol abuse may help identify co-infected patients at risk of subsequent HIV virological rebound.

Ribavirin and abacavir drug interaction in HIV-HCV coinfected patients: fact or fiction?

OBJECTIVE(S): To examine the impact of ribavirin and abacavir coadministration on hepatitis C virus (HCV) virological response and trough ribavirin plasma concentration (Cmin) in HIV-HCV coinfected patients. DESIGN: Pharmacokinetic substudy on patients from the ANRS CO-13 HEPAVIH cohort. METHODS: Patients receiving ribavirin-pegylated interferon for whom a ribavirin steady state Cmin was prospectively determined were included. Rapid virological response (RVR), early virological response (EVR) and sustained virological response (SVR) as well as HCV-RNA decline were evaluated. RESULTS: Overall, 124 HIV-HCV coinfected patients (95% on antiretroviral therapy) were enrolled. Of these patients, 22% received abacavir. The overall median (interquartile range) ribavirin Cmin was 1.6 mg/l (1.2-2.2) with no statistical difference between abacavir users and nonusers [1.5 mg/l (0.99-2.1) and 1.7 (1.2-2.3), P = 0.15]. RVR and EVR were 52 and 72%, respectively. There was no difference observed in the proportion of abacavir users vs. nonusers achieving RVR (respectively 59 vs. 50%, P = 0.40) or EVR (72 vs. 73%, P = 0.94), or in the HCV-RNA decline at week 4 [-2.24 log(10) IU/ml, (-3.58; -0.81) and -1.27 (-2.8; -0.47) P = 0.28] or at week 12 [-1.76 log(10) IU/ml (-3.67; -0.35) and -1.85 (-3.13; -1.13) (P = 0.58)]. The SVR rate was 45% for abacavir users and 24% for abacavir nonusers, but the difference was not statistically significant (P = 0.059). CONCLUSION: In our study, there was no evidence that abacavir affected HCV treatment outcomes and the ribavirin Cmin was similar in abacavir users and nonusers, confirming the absence of pharmacokinetic interaction between abacavir and ribavirin. An abacavir-containing regimen is, therefore, a well tolerated treatment alternative for coinfected patients starting HCV treatment.

Erythrocyte and plasma ribavirin concentrations in the assessment of early and sustained virological responses to pegylated interferon-alpha 2a and ribavirin in patients coinfected with hepatitis C virus and HIV.

OBJECTIVES: To determine the relationship between erythrocyte and plasma ribavirin concentrations in hepatitis C virus (HCV)/HIV-coinfected patients, and to correlate ribavirin exposure with early and sustained virological response (EVR and SVR) and haemoglobin level reductions. METHODS: Clinical and biological data from 68 HCV/HIV-coinfected patients were recorded at baseline, week 4 (W4), week 12 and at 24 weeks after completion of treatment. Plasma and erythrocyte ribavirin concentrations were determined 12 h after the final ribavirin dose (C(min)). RESULTS: Erythrocyte ribavirin concentrations were 100-fold higher than plasma concentrations, with a significant relationship between them (P < 0.05). In patients with HCV genotype 1 or 4, a plasma ribavirin C(min) threshold of 1.95 mg/L at W4 tended to predict EVR [sensitivity 44%; specificity 87%; AUC 0.67 (95% CI 0.50-0.84)] and was predictive of SVR [sensitivity 58%; specificity 84%; AUC 0.71 (95% CI 0.51-0.90)]. Among patients with these HCV genotypes, an erythrocyte ribavirin C(min) threshold of 146 mg/L at W4 was found to be the best value for discriminating between responders and non-responders for both EVR [sensitivity 67%; specificity 75%; AUC 0.58 (95% CI 0.24-0.93)] and SVR [sensitivity 50%; specificity 80%; AUC 0.70 (95% CI 0.39-1.01)]. We also demonstrated a significant relationship between reduced haemoglobin levels and plasma ribavirin C(min) at W4 (P = 0.05). CONCLUSIONS: Therapeutic drug monitoring may be useful for the management of anti-HCV treatment in HCV/HIV-coinfected patients.

Lack of TGF-ß production by hepatitis C virus-specific T cells during HCV acute phase is associated with HCV clearance in HIV coinfection.

BACKGROUND & AIMS: Immunity and genetic factors govern the recovery from acute hepatitis C virus (HCV) infection. No predictive factors have been yet identified in patients coinfected with the human immunodeficiency virus (HIV). We investigated whether early T cell responses to HCV producing transforming-growth-factor beta (TGF-ß) predict the outcome of acute HCV coinfection, independently of the IL-28B gene polymorphism. METHODS: Intracellular cytokine staining assays against HCV-core, E1, NS2, and NS4 overlapping peptides were used for the analysis of peripheral HCV-specific TGF-ß-producing T cells. Patients were genotyped for IL-28B polymorphisms. Healthy donors' samples were tested as controls. Twenty-four acute hepatitis C-HIV+ patients were followed-up for 15 months defining two groups: (A) Recovered (n=16, 5 spontaneous recoveries, 11 sustained virologic response after treatment), (B) Chronic HCV (n=8, 4 spontaneous chronic course, 4 therapeutic failures). RESULTS: During the acute pretreatment phase, core/NS2-specific TGF-ß-producing CD4+ and/or CD8+ T cells were detected in 8/24 (33%) patients. Lack of anti-HCV TGF-ß+ cells was characteristic of healthy donors and Group A, except for 2 cases, with frequencies significantly lower than in Group B (p=0.04 and 0.01), and was associated with recovery in 14/16 cases. Presence of anti-HCV TGF-ß+ cells was associated with persistent viremia in 6/8 cases (p=0.005). This profile remained stable over time. Such TGF-ß production was independent of the rs129679860 SNP (p=1.0) which was not associated with recovery (p=1.0). CONCLUSIONS: During acute hepatitis C, pre-therapeutic HCV-specific TGF-ß-producing T cells are a new marker independent of the IL-28B gene polymorphism, predicting the lack of spontaneous or therapeutic HCV clearance.

Influence of interferon-based therapy on liver fibrosis progression in HIV/HCV coinfected patients: a retrospective repeated liver biopsy analysis.

BACKGROUND & AIMS: Hepatitis C virus (HCV) coinfection is one of the leading causes of mortality in human immunodeficiency virus-infected patients. The current standard of care leads to cure only in a part of these patients. The course of the disease is determined by the rapidity of liver fibrosis progression (LFP). The influence of interferon on LFP in coinfected patients has yet not been evaluated by comparative liver biopsies. METHODS: We extracted data of patients who had serial liver biopsies from a hospital database. Histopathological findings were compared to factors possibly linked to fibrosis progression. Furthermore, we studied the impact of response to interferon treatment on fibrosis progression. RESULTS: Hundred and twenty-six patients were included, 68 had received anti-HCV treatment, and 58 had not. The median time between the first and the last biopsy was 4 years. Worsened fibrosis was observed in 35 of 58 (60%) untreated patients, and 22 of 50 (44%) patients in the nonresponder/relapser group, and in 5 out of 18 (28%) in the SVR group. Liver fibrosis evolution was significantly better in patients achieving a SVR than in untreated and NR/R patients (p<0.02, odds-ratio [95% CI] for improvement vs. stability vs. worsening=3.16 [1.24-8.07]). This result persisted after adjustment for known predictors of liver fibrosis progression, HBsAg, CD4, and alcohol consumption: adjusted odds ratio=2.89 [1.09-7.68], p=0.03. CONCLUSIONS: HCV treatment can stop fibrosis progression and induce its regression. Nonresponders to treatment may even have a fast fibrosis progression. It remains to be clarified if the same factors that induce nonresponse to treatment may also induce faster fibrosis progression.

Effect of antiretroviral drugs on the quality of semen.

The aim of this cross-sectional study was to determine which antiretroviral drugs (ARVs) are associated with changes in the characteristics of semen and the impact of these ARVs according to their score penetration into the male genital compartment. Data from 144 men infected with HIV-1 enrolled in an Assisted Reproductive Technology program were analyzed retrospectively. A seminal penetration score of ARV was based on the available literature. The nonparametric Kruskal-Wallis test and chi-square test were used. There was no difference on sperm parameters between NRTI, NNRTI, or PI regimen. In patients receiving NRTIs or PIs no differences were observed between antiretrovirals of these classes. However, in patients receiving NNRTIs, nevirapine (n = 22) was associated with a higher percentage of progressively motile spermatozoa (P < 0.0001) versus efavirenz (n = 38) as well as vitality (P = 0.0004). No relationship was observed between semen quality and the penetration score. NRTIs and PIs were not associated with any semen changes. Nevirapine was associated with a better quality of semen versus efavirenz. It would be of interest to validate, improve and test our penetration score in a prospective study.

Treatment of acute hepatitis C in human immunodeficiency virus-infected patients: the HEPAIG study.

UNLABELLED: Acute hepatitis C continues to be a concern in men who have sex with men (MSM), and its optimal management has yet to be established. In this study, the clinical, biological, and therapeutic data of 53 human immunodeficiency virus (HIV)-infected MSM included in a multicenter prospective study on acute hepatitis C in 2006-2007 were retrospectively collected and analyzed. The mean hepatitis C virus (HCV) viral load at diagnosis was 5.8 ± 1.1 log(10) IU/mL (genotype 4, n = 28; genotype 1, n = 14, genotype 3, n = 7). The cumulative rates of spontaneous HCV clearance were 11.0% and 16.5% 3 and 6 months after diagnosis, respectively. Forty patients were treated, 38 of whom received pegylated interferon and ribavirin. The mean duration of HCV therapy was 39 ± 17 weeks (24 ± 4 weeks in 14 cases). On treatment, 18/36 (50.0%; 95% confidence interval 34.3-65.7) patients had undetectable HCV RNA at week 4 (RVR), and 32/39 (82.1%; 95 confidence interval 70.0-94.1) achieved sustained virological response (SVR). SVR did not correlate with pretreatment parameters, including HCV genotype, but correlated with RVR (predictive positive value of 94.4%) and with effective duration of HCV therapy (64.3% for 24 ± 4 weeks versus 92.0% for longer treatment; P = 0.03). CONCLUSION: The low rate of spontaneous clearance and the high SVR rates argue for early HCV therapy following diagnosis of acute hepatitis C in HIV-infected MSM. Pegylated interferon and ribavirin seem to be the best option. The duration of treatment should be modulated according to RVR, with a 24-week course for patients presenting RVR and a 48-week course for those who do not, irrespectively of HCV genotype.

Impact of hepatitis C and liver fibrosis on antiretroviral plasma drug concentrations in HIV-HCV co-infected patients: the HEPADOSE study.

OBJECTIVES: To compare plasma antiretroviral concentrations in HIV-HCV co-infected and in matched HIV mono-infected patients. METHODS: This was a cross-sectional, observational study. Antiretroviral trough concentrations (C(min)) in plasma were measured in HIV-HCV co-infected patients with liver disease documented by liver biopsy, matched with HIV mono-infected patients according to gender and antiretroviral treatment. C(min) values in serum were measured using an HPLC method. Statistical analysis was performed using the Wilcoxon test. RESULTS: Seventy-three HIV-HCV co-infected patients and 66 HIV-infected patients were enrolled; 70% of patients were receiving a protease inhibitor (PI)- and 30% a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Among the 73 co-infected patients, 27 had a fibrosis score (Fibrotest(®)) of F4. Abacavir was the only nucleoside reverse transcriptase inhibitor whose trough concentrations differed between the co-infected and mono-infected groups. PI median plasma C(min) values were not different in the two groups, except for lopinavir, with a lower C(min) in the co-infected group than in the HIV-infected group (median 3673 versus 5990 ng/mL, P=0.04), and nelfinavir, with significantly higher concentrations in the co-infected group. Seventy-five percent of co-infected patients scoring F4, 33% of those scoring F0-F3 and 12% of HIV-infected patients were underdosed (P=0.02). Co-infected patients receiving an NNRTI had a higher plasma C(min) than HIV-infected patients; median C(min) was 3583 versus 1494 ng/mL (P=0.025) and 5331 versus 3954 ng/mL (P=0.10) for efavirenz and nevirapine, respectively. Overall, there was a greater proportion of co-infected patients with high concentrations of both NNRTIs (15/23) compared with HIV mono-infected patients (5/21) (P=0.008), especially in co-infected patients with an advanced liver fibrosis stage. CONCLUSIONS: Median plasma C(min) values differed significantly between HIV and HIV-HCV co-infected patients for abacavir, lopinavir and efavirenz. NNRTIs were strongly overdosed in HIV-HCV co-infected patients.