Reduced healthcare utilization following successful hepatitis C virus treatment in HIV‐co‐infected patients with mild liver disease

New direct‐acting antivirals (DAA) for hepatitis C virus (HCV) infection have achieved high cure rates in many patient groups previously considered difficult‐to‐treat, including those HIV/HCV co‐infected. The high price of these medications is likely to limit access to treatment, at least in the short term. Early treatment priority is likely to be given to those with advanced disease, but a more detailed understanding of the potential benefits in treating those with mild disease is needed. We hypothesized that successful HCV treatment within a co‐infected population with mild liver disease would lead to a reduction in the use and costs of healthcare services in the 5 years following treatment completion. We performed a retrospective cohort study of HIV/HCV‐co‐infected patients without evidence of fibrosis/cirrhosis who received a course of HCV therapy between 2004 and 2013. Detailed analysis of healthcare utilization up to 5 years following treatment for each patient using clinical and electronic records was used to estimate healthcare costs. Sixty‐three patients were investigated, of whom 48 of 63 (76.2%) achieved sustained virological response 12 weeks following completion of therapy (SVR12). Individuals achieving SVR12 incurred lower health utilization costs (£5000 per‐patient) compared to (£10 775 per‐patient) non‐SVR patients in the 5 years after treatment. Healthcare utilization rates and costs in the immediate 5 years following treatment were significantly higher in co‐infected patients with mild disease that failed to achieve SVR12. These data suggest additional value to achieving cure beyond the prevention of complications of disease.     

Liver stiffness measurements to assess progression of fibrosis in HCV‐infected patients with inherited bleeding disorders

Summary. Hepatitis C is a major co‐morbidity in patients with inherited bleeding disorders, leading to progressive liver fibrosis and eventually cirrhosis. Liver stiffness measurement (LSM) is a non‐invasive way of assessing the extent of liver fibrosis. This article describes our experience with serial LSM to assess prospectively progression of fibrosis in a cohort of patients with inherited bleeding disorders and chronic hepatitis C. A total of 84 patients underwent serial LSMs, with a median interval of 3.7 years. The change in LSM results over time was assessed. Overall, there was no significant difference between the median results of LSM 1 and LSM 2. The median result of LSM 2 was low (6.6 kPa), after a median duration of infection of 37 years. On the individual level, deterioration of LSM results of more than 2 kPa was seen in 13 patients (16%), 44 patients (52%) remained stable and 27 patients (32%) showed improvement of LSM results of more than 2 kPa. These results are comparable with those of paired liver biopsy studies. LSM appears to be a good alternative for liver biopsies in patients with hepatitis C and inherited bleeding disorders, although the interpretation of the unexpected improvement we found in some of our patients is not straightforward. LSMs will be repeated in our patient population in a few years to be able to better assess the value of serial LSM.     

Documented rapid course of hepatic fibrosis between two biopsies in patients coinfected by HIV and HCV despite high CD4 cell count

In HIV/hepatitis C virus (HCV)-coinfected patients, it is recommended to repeat liver biopsy every 3 years when anti-HCV treatment is not indicated. We studied fibrosis progression in HIV/HCV-coinfected patients, who were not receiving anti-HCV treatment, on the basis of two successive liver biopsies. Thirty-two patients were retrospectively included. Twenty-six patients (79%) were on antiretroviral treatment at the first biopsy. The mean CD4 cell count was 470 +/- 283/mm(3). Three patients were staged F2 and the remainder F0/F1. The median interval between the two biopsies was 49 (24-80) months. At the second biopsy, the stage distribution was F0 0%, F1 41% (n = 13), F2 34% (n = 11), F3 19% (n = 6) and F4 6% (n = 2). The mean fibrosis progression rate (FPR) was 0.25 points/year. Nine patients (28%) were considered as rapid fibrosis progressors (progression by more than two points) and their FPR was 0.5 point/year; comparison of these subjects with the other 23 patients showed no relation between FPR and age, alcohol consumption, CD4+ cell count, HIV viral load, HCV genotype, aspartate aminotransferase or alanine aminotransferase. Analysis of the treatment received between the two liver biopsies did not find any correlation between liver FPR and a specific compound. Fifteen patients started anti-HCV therapy based on the second biopsy. Liver fibrosis in HIV/HCV-coinfected patients should be evaluated at least every 3 years, as nine of 32 (28%) of our patients progressed by at least two fibrosis points despite a high CD4+ cell count. The second biopsy showed that 15 patients (45%) qualified for anti-HCV therapy. Development of noninvasive methods of fibrosis evaluation should permit more frequent monitoring.     

Risk factors for advanced liver fibrosis in HIV‐infected individuals: role of antiretroviral drugs and insulin resistance

Summary. Liver damage may result from multiple factors in HIV‐infected patients. The availability of reliable noninvasive tools to measure liver fibrosis has permitted the screening of large patient populations. Cross‐sectional study of all consecutive HIV outpatients who underwent examination by transient elastometry (FibroScan) at one HIV reference clinic during 2007. Advanced liver fibrosis (ALF) was defined as hepatic stiffness >9.5 kilopascals, which corresponds to Metavir stages F3‐F4 in the liver biopsy. A total of 681 consecutive HIV‐infected patients (64% injecting drug users; mean age 43; 78% male; 98% on antiretroviral therapy) had at least one valid FibroScan evaluation. ALF was diagnosed in 215 (32%) of them. In the univariate analysis, ALF was significantly associated with older age, low CD4 counts, chronic hepatitis C, past alcohol abuse, elevated ALT, high triglycerides, low cholesterol, high homeostasis model assessment (HOMA) index and exposure to didanosine and/or stavudine. In a multivariate model (OR, 95% CI), chronic hepatitis C (2.83, 1.57–5.08), past alcohol abuse (2.26, 1.37–3.74), exposure to didanosine and/or stavudine (1.85, 1.14–3.01), high HOMA index (1.25, 1.04–1.51), older age (1.09, 1.05–1.14) and elevated ALT (1.04, 1.03–1.06) remained as independently associated with ALF. Therefore, in addition to chronic hepatitis C and alcohol abuse, insulin resistance and/or exposure to dideoxy‐nucleosides may contribute to ALF in HIV‐infected patients.     

Liver transplantation for HIV/hepatitis C virus co‐infected patients

Since the introduction of antiretroviral therapy (ART) in the mid‐1990s, AIDS‐related death has been dramatically reduced, and hepatitis‐C‐virus (HCV)‐related liver failure or hepatocellular carcinoma has currently become the leading cause of death in HIV/HCV co‐infected patients. Liver transplantation may be one of the treatments of choices in such cases, but the indications for transplantation, perioperative management including both HIV and HCV treatments, immunosuppression and the prevention/treatment of infectious complications are all still topics of debate. With the improved understanding of the viral behaviors of both HIV and HCV and the development of novel strategies, especially to avoid drug interactions between ART and immunosuppression, liver transplantation has become a realistic treatment for HIV/HCV co‐infected patients.     

HIV‐positive men who have sex with men are at high risk of development of significant liver fibrosis after an episode of acute hepatitis C

Acute hepatitis C virus infection remains a major health concern in human immunodeficiency virus(HIV)‐infected men who have sex with men (MSM). New direct‐acting antiviral agent (DAA) combination therapy has not yet been approved for the treatment for acute hepatitis C virus(HCV), thereby potentially causing deferral of HCV treatment. Therefore, we aimed to study the course of liver disease after an episode of acute HCV. This study is a retrospective single‐centre cohort of HIV‐positive MSM with acute HCV infection. Liver fibrosis was estimated by Fibroscan^® and Fibrotest^®. Liver‐related and non‐liver‐related outcomes were documented. Overall 213 episodes of acute HCV infection in 178 men were documented. Median follow‐up for all included patients was 38.7 months. Spontaneous HCV clearance was found in 10.8% of patients, which was significantly associated with older age, lower HCV RNA levels, and higher ALT levels upon initial acute HCV diagnosis. Treatment with interferon‐based therapy was initiated in 86.3% of cases, resulting in a sustained virological response(SVR) rate of 70.7%. After 3 years’ follow‐up, significant liver fibrosis of METAVIR F2 stage or higher was found in 39.4% of patients after first acute HCV diagnosis. Higher age, physician‐declared alcoholism, and nonresponse to acute HCV therapy were independently associated with higher fibrosis stages. Ten patients died during the observation period (IR 1.4/100 patient‐years) and four during interferon treatment. Significant liver fibrosis is a common finding in HIV‐positive MSM following acute HCV infection despite high treatment uptake and cure rates, suggesting the need for close liver disease monitoring particularly if HCV treatment is deferred.     

More improvement than progression of liver fibrosis following antiretroviral therapy in a longitudinal cohort of HIV‐infected patients with or without HBV and HCV co‐infections

We examined the effect of combination antiretroviral therapy (cART) on liver fibrosis among HIV‐infected patients with or without hepatitis B (HBV) or C virus (HCV) co‐infection. This was a retrospective cohort study of HIV‐infected patients receiving cART during 2004‐2016. Liver fibrosis was assessed using Fibrosis‐4 (FIB‐4) score with three classifications: Class 1, <1.45; Class 2, 1.45‐3.25; Class 3, >3.25. Of 3900 participants, 68.6% were HIV mono‐infected, 5.3% were HIV/HBV co‐infected, 23.8% were HIV/HCV co‐infected and 2.3% were HIV/HBV/HCV co‐infected. Participants received follow‐up treatment (median was 3.3 years). Improvement to a lower class was observed in Class 2 (52.6%) and Class 3 (74.2%), respectively. Progression to a higher class was observed in 12.8% and 5.0% in Class 1 and Class 2, respectively, and with a median time of 5.7 months. For improvement to lower classes, older age, male, Dai ethnicity, injection drug use, HCV co‐infection and tenofovir for treatment were negative predictors, but in Class 3 of FIB‐4 and time‐updated increases in CD4 count from baseline were positive predictors. For progression to higher classes, older age, male, Jingpo ethnicity and HCV co‐infection were positive predictors, while baseline CD4 count and in Class 2 of FIB‐4 were negative predictors. Improvement to lower class linked with decreased mortality risk among patients in Class 3. Early cART initiation for HIV‐infected patients with and without hepatitis co‐infections may mitigate or slow down some of liver fibrosis, but special attention should be given to those who are older, male, co‐infected with HCV.     

Correlation of transient elastography with APRI and FIB‐4 in a cohort of patients with congenital bleeding disorders and HCV or HIV/HCV coinfection

Summary. Patients with inherited bleeding disorders frequently suffer from chronic hepatitis C virus (HCV) mono‐ or human immunodeficiency virus (HIV)/HCV coinfection. Non‐invasive markers for liver fibrosis are warranted for these patients. We tested a large cohort of haemophilic patients with HCV mono‐ or HIV/HCV coinfection for correlation of transient elastography (TE) with two simple surrogate markers of liver fibrosis and for differences in fibrosis stages according to these markers. We prospectively enrolled HCV‐positive patients with congenital bleeding disorders with or without HIV coinfection. Liver function tests and platelet counts were determined and TE was performed. Aspartate aminotransferase‐to‐platelet ratio index (APRI) and a simple index called FIB‐4 were calculated and results were correlated with TE. A total number of 174 patients were included (23% HCV, 36% HIV/HCV coinfected, 33% with cleared HCV and 8% with ongoing HIV but cleared HCV). TE correlated significantly with APRI and FIB‐4 (r = 0.60; P < 0.001 and r = 0.54; P < 0.001 respectively). This correlation was pronounced in patients with ongoing HCV infection (r = 0.67; P < 0.001 and r = 0.60; P < 0.001). Prediction of advanced fibrosis resulted in concordance rates >80% with combinations of TE plus APRI and APRI plus FIB‐4. HIV/HCV coinfected patients did not present with advanced fibrosis stages when compared with HCV‐monoinfected patients. Combinations of two non‐invasive markers may significantly reduce the number of liver biopsies in patients with bleeding disorders and advanced liver fibrosis. Furthermore, our data support previous studies that observed a favourable outcome in patients with HIV/HCV and a preserved immune function in times of highly active antiretroviral therapy.     

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

Summary. 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 enrolment 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 mm³ 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.     

The prevalence of hepatitis C virus (HCV) infection in HIV‐positive individuals in the UK – trends in HCV testing and the impact of HCV on HIV treatment outcomes

Summary. We examined the prevalence of hepatitis C virus (HCV) infection among HIV‐positive individuals in the UK, trends in HCV testing and the impact of HCV on HIV treatment outcomes. Trends over time in HCV prevalence were calculated using each patient’s most recent HCV status at the end of each calendar year. Logistic regression was used to identify factors associated with having a HCV antibody test, and Cox regression was used to determine whether HCV status was associated with the time to experiencing an immunological response to highly active antiretroviral treatment (HAART), time to virological response and viral rebound. Of the 31 765 HIV‐positive individuals seen for care between January 1996 and September 2007, 20 365 (64.1%) individuals were tested for HCV, and 1807 (8.9%) had detectable HCV antibody. The proportion of patients in follow‐up ever tested for HCV increased over time, from 782/8505 (9.2%) in 1996 to 14 280/17 872 (79.9%) in 2007. Nine thousand six hundred and sixty‐nine individuals started HAART for the first time in or after January 2000, of whom, 396 (4.1%) were HCV positive. Presence of HCV infection did not affect initial virological response, virological rebound or immunological response. The cumulative prevalence of HCV in the UK CHIC Study is 8.9%. Despite UK guidelines, over 20% of HIV‐positive individuals have not had their HCV status determined by 2007. HCV infection had no impact on HIV virological outcomes or immunological response to HIV treatment. The long‐term impact on morbidity and mortality remain to be determined.     

Bacterial translocation and clinical progression of HCV‐related cirrhosis in HIV‐infected patients

The aim of the study was to evaluate whether bacterial translocation (BT) predicts the clinical outcome in HIV/HCV‐coinfected patients with compensated cirrhosis. A cohort of 282 HIV/HCV‐coinfected patients with cirrhosis and no previous liver decompensation (LD) was recruited. Serum levels of the DNA sequences encoding the well‐conserved 16S rRNA subunit (16S rDNA), the lipopolysaccharide (LPS) and soluble CD14 (sCD14) at diagnosis of cirrhosis were measured. Primary endpoint was the emergence of the first LD and/or death of any cause. Secondary endpoints were LD, liver‐related death (LRD) and death of any cause. After a median (Q1‐Q3) follow‐up of 51 (27‐72) months, 67 patients (24%; 95% CI: 19‐29) developed their first LD or died during follow‐up. Baseline levels of 16S rDNA, LPS and sCD14 were not associated with the probability of developing the primary endpoint of the study. The mean (SD) survival time free of LD and/or death according to levels of 16S rDNA (<83, 83‐196, 197‐355, >355 [copies/μL]) was 78 (5), 72 (5), 81 (4) and 82 (4) months, respectively (P = .5). The corresponding figures for LPS (<0.1, 0.1‐0.6, 0.6‐1.5, > 1.5 [IU/mL]) were 76 (5), 71 (5), 77 (5) and 81 (4) months, respectively (P = .4). Baseline levels of BT serum markers were not associated with any of the secondary endpoints analysed in the study. Thus, BT does not seem to be a relevant predictor of clinical outcome in HIV/HCV‐coinfected patients with compensated cirrhosis.