Changes in liver fibrosis in HIV/HCV‐coinfected patients following different outcomes with peginterferon plus ribavirin therapy

There is scarce information about the impact of antiviral treatment on subsequent progression of liver fibrosis in HIV‐infected patients with chronic hepatitis C who experience different outcomes following peginterferon‐ribavirin therapy. We conducted a retrospective study of a cohort of HIV/HCV‐coinfected patients with longitudinal assessment of liver fibrosis using elastometry. Patients were split out into four groups according to the prior peginterferon‐ribavirin response: sustained virological response (SVR), relapse (R), partial response (PR) and null response (NR). A group of untreated, coinfected patients was taken as control. Significant liver fibrosis progression (sLFP) was defined as a shift from baseline Metavir estimates ≤F2 to F3‐F4, or by >30% increase in liver stiffness in patients with baseline F3‐F4. Conversely, significant liver fibrosis regression (sLFR) was defined as a shift from baseline Metavir estimates F3‐F4 to ≤F2, or by >30% reduction in liver stiffness in patients that kept on F3‐F4. A total of 498 HIV/HCV‐coinfected patients were examined. They were classified as follows: 138 (27.7%) SVR, 40 (8%) R, 61 (12.2%) PR, 71 (14.3%) NR and 188 (37.8%) naive. After a mean follow‐up of 53.3 months, sLFP occurred less frequently in patients with SVR (7.2%) compared with R (25%; P = 0.002), PR (23%; P = 0.002), NR (29.6%; P < 0.001) and naïve (19.7%; P = 0.002). Conversely, sLFR was 26.1% in SVR compared with 10% in R (P = 0.03), 14.8% in PR (P = 0.06), 16.9% in NR (P = 0.07) and 10.6% in naïve (P < 0.001). Sustained clearance of serum HCV‐RNA following a course of antiviral treatment is the major determinant of liver fibrosis regression in HIV/HCV‐coinfected patients.     

Pretreatment assessment and predictors of hepatitis C virus treatment in US veterans coinfected with HIV and hepatitis C virus

The US Department of Veterans Affairs (VA) cares for many human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients. VA treatment recommendations indicate that all HIV/HCV-coinfected patients undergo evaluation for HCV treatment and list pretreatment assessment tests. We compared clinical practice with these recommendations. We identified 377 HIV/HCV-coinfected veterans who began HCV therapy with pegylated interferon and ribavirin and 4135 HIV/HCV-coinfected veterans who did not but were in VA care at the same facilities during the same period. We compared laboratory and clinical characteristics of the two groups and estimated multivariate logistic regression models of receipt of HCV treatment. Overall, patients had high rates of receipt of tests necessary for HCV pretreatment assessment. Patients starting HCV treatment had higher alanine aminotransferase (ALT), lower creatinine, higher CD4 counts and lower HIV viral loads than patients not starting HCV treatment. In the multivariate model, positive predictors of starting HCV treatment included being non-Hispanic whites, having higher ALTs, lower creatinines, higher HCV viral loads, higher CD4 counts, undetectable HIV viral loads and receiving HIV antiretrovirals. A history of chronic mental illness and a history of hard drug use were negative predictors. Most HIV/HCV-coinfected patients received the necessary HCV pretreatment assessments, although rates of screening for hepatitis A and B immunity can be improved. Having well-controlled HIV disease is by far the most important modifiable factor affecting the receipt of HCV treatment. More research is needed to determine if the observed racial differences in starting HCV treatment reflect biological differences, provider behaviour or patient preference.     

Anti-hepatitis C virus treatment may prevent the progression of liver fibrosis in non-responder human immunodeficiency virus/hepatitis C virus coinfected patients

AimTo evaluate changes in liver histology in patients with human immunodeficiency virus/hepatitis C virus coinfection non-responders to a suboptimal Interferon + Ribavirine regimen.Materials and methodsWe investigated 49 patients with two sequential liver biopsies: 18 were non-responders to Interferon + Ribavirine treatment (Group hepatitis C virus Rx) administered after the 1st liver biopsy who underwent a 2nd liver biopsy after a median period of 3.92 year and 31 were patients who remained untreated for hepatitis C virus disease (Group hepatitis C virus untreated) after the 1st liver biopsy because of refusal and underwent a 2nd liver biopsy after a median period of 5.05-years. Most patients in both groups were under highly active antiretroviral therapy. At the time of 1st liver biopsy similar degrees of necro-inflammation, fibrosis and steatosis were observed in both groups. Changes in liver lesions between 1st and 2nd liver biopsys were adjusted for different intervals between liver biopsys by a mathematic formula.ResultsLiver fibrosis did not change in 88.9% of patients in Group hepatitis C virus Rx and in 77.4% in Group hepatitis C virus untreated. A marked deterioration in liver fibrosis was observed in 5 (16%) patients in Group hepatitis C virus untreated and in none in Group hepatitis C virus treated. Necro-inflammation and steatosis remained substantially unchanged in both groups.ConclusionLiver histology remained substantially unchanged in human immunodeficiency virus/hepatitis C virus patients non-responder to anti-hepatitis C virus therapy over 4 years observation, suggesting an effective anti-hepatitis C virus early treatment for all hepatitis C virus/human immunodeficiency virus coinfected patients who can reasonably tolerate therapy.     

CCR5 as a Natural and Modulated Target for Inhibition of HIV

Human immunodeficiency virus type 1 (HIV-1) infection of target cells requires CD4 and a co-receptor, predominantly the chemokine receptor CCR5. CCR5-delta32 homozygosity results in a truncated protein providing natural protection against HIV infection—this without detrimental effects to the host—and transplantation of CCR5-delta32 stem cells in a patient with HIV (“Berlin patient”) achieved viral eradication. As a more feasible approach gene-modification strategies are being developed to engineer cellular resistance to HIV using autologous cells. We have developed a dual therapeutic anti-HIV lentiviral vector (LVsh5/C46) that down-regulates CCR5 and inhibits HIV-1 fusion via cell surface expression of the gp41-derived peptide, C46. This construct, effective against multiple strains of both R5- and X4-tropic HIV-1, is being tested in Phase I/II trials by engineering HIV-resistant hematopoietic cells.     

HIV/HCV coinfection and the risk of cardiovascular disease: A meta‐analysis

The emergence of improved antiretroviral therapy has increased the life expectancy of human immunodeficiency virus (HIV)‐infected individuals, although there is an increased susceptibility to developing cardiovascular diseases (CVD). The risk for CVD is purported to be even higher among people with HIV and hepatitis C virus (HCV) coinfection because of the increased inflammatory response, which may synergistically impact CVD risk. However, studies comparing CVD outcomes between HIV alone and HIV/HCV individuals have been discordant. Accordingly, we conducted a meta‐analysis to clarify and quantify the association between HIV/HCV coinfection and the risk for CVD. We searched EMBASE, CINAHL, Google Scholar, PubMed, and Web of Science from inception to December 2016 to identify studies that provided information on HIV/HCV coinfection and CVD, defined as coronary artery disease, congestive heart failure and stroke. We used a random‐effects model to abstract and pool data on the hazard ratios (HRs) for CVD. HRs were adjusted for traditional CVD risk factors including age, sex, smoking, hypertension, diabetes and LDL cholesterol. Among the 283 articles reviewed, four cohort studies met inclusion criteria with a total of 33 723 participants. The pooled adjusted HRs for the association between HIV/HCV coinfection and CVD were 1.24 (95% CI: 1.07‐1.40) compared to HIV monoinfection. The test for heterogeneity was not statistically significant (I²=0.0%, P=.397). In conclusion, individuals with HIV/HCV coinfection had an increased CVD risk compared to those with HIV monoinfection. More research is needed to further examine the nature of this association, and response to traditional risk‐reduction therapies.     

Cognitive function, mood and health-related quality of life in hepatitis C virus (HCV)-monoinfected and HIV/HCV-coinfected individuals commencing HCV treatment

OBJECTIVES: The aim of the study was to examine cognitive function, mood and health-related quality of life (HRQOL), and their interrelationships, among hepatitis C virus (HCV)-monoinfected and HIV/HCV-coinfected individuals. METHODS: Baseline neuropsychological and HRQOL measures of HCV-monoinfected and HIV/HCV-coinfected individuals commencing HCV treatment were examined from a prospective cohort study conducted between April 2003 and August 2005 in Sydney, Australia. Participants' neuropsychological performance and HRQOL were measured using computer-based battery, Trail Making Tests (TMT), Depression Anxiety Stress Scales (DASS), the Hepatitis Quality of Life Questionnaire (HQLQ), and the Visual Analogue Scale (VAS). Neuropsychological measures of HCV-infected patient groups were compared with those of two control groups consisting of HIV-monoinfected and uninfected individuals. RESULTS: Similar cognitive function, mood and HRQOL were found in HCV-monoinfected (n=19) and HIV/HCV-coinfected (n=15) individuals. When compared with the HIV-monoinfected (n=30) and uninfected control (n=30) groups, subtle cognitive impairment in attention was found in the HIV/HCV-coinfected group (P<0.05). Twenty-one percent of the HCV-monoinfected group were classified as having cognitive impairment compared with 10% or less in the other groups. Sociodemographic characteristics, mood, HRQOL and HCV indices did not correlate with cognitive function. CONCLUSIONS: Our findings indicate no statistically significant difference in neuropsychological and HRQOL impairments between HIV/HCV-coinfected individuals with nonadvanced HIV disease and HCV-monoinfected individuals. This lack of significant difference may relate to the relatively small study population.     

Binding of HCV E2 to CD81 induces RANTES secretion and internalization of CC chemokine receptor 5

Hepatitis C virus (HCV) infection has been shown to be associated with reduced expression of the CC chemokine receptor (CCR) 5, and reduced responsiveness of lymphocytes to chemokines. However, the mechanism by which HCV alters CCR5 expression remains unclear. Here, we investigated whether altered CCR5 expression in hepatitis C results from interactions of CD81 with the HCV E2 protein. Peripheral blood mononuclear cells (PBMC) from HCV-negative individuals were prepared by Ficoll density gradient separation. PBMC subpopulations (CD4+, CD8+ lymphocytes, CD19+ B cells, natural killer (NK) cells and monocyte-derived dendritic cells) were isolated and stimulated with immobilized HCV E2, and changes in CCR5 expression and CC-chemokine secretion were determined. Migration assays were performed using a 5-microm nitrocellulose filter microchamber system according to the manufacturer's recommendations. Exposure of PBMC to HCV E2 induced a dose-dependent release of regulated on activation normal T-cell-expressed and secreted (RANTES), down-regulation of CCR5 expression and intracellular accumulation of CCR5. This effect was blocked by preincubation of PBMC with anti-CD81. RANTES release following exposure to HCV E2 was mainly attributable to CD8+ cells. After exposure to HCV E2 markedly fewer CD8-positive lymphocytes were attracted by RANTES when compared with CD8+ cells that were studied in the absence of HCV E2. Our results suggest that interaction of HCV E2 with CD81 leads to increased RANTES secretion by CD8+ lymphocytes which induces down-regulation of CCR5 surface via receptor internalization resulting in altered lymphocyte migration.     

Intrahepatic Expression of C-C Motif ligand 5 in Patients with Chronic Hepatitis B

Background: C-C motif ligand 5 (CCL5) is reported to play a key role in acute and chronic liver diseases. However, the association between CCL5 and chronic hepatitis B (CHB) remains to be explored. We aimed to investigate the CCL5 expression in the liver tissues of CHB patients and compared the CCL5 expression among CHB patients with different stages of liver inflammation and fibrosis. Methods: Liver tissue specimens from 51 CHB patients who underwent liver biopsy and twelve healthy liver donors were included in the present study. CCL5 expression in the liver tissues was analyzed using immunohistochemistry. The hepatic inflammation grades and fibrotic stages of CHB patients were assessed by the Scheuer classification system. Results: Livers of CHB patients exhibited significantly accumulated CCL5+ cells when compared to those of healthy controls (42.80 ± 4.37 vs. 7.25 ± 0.99/HPF, P < .001). CHB patients with higher hepatic inflammation grades had more CCL5+ cells in their livers than those with lower grades (P < .05). However, the numbers of CCL5+ cells were not correlated with the fibrotic stages in CHB patients (r = .073, P = .61). The number of CCL5+ cells in the liver tissues of CHB patients was positively correlated with alanine transaminase levels (r = .278, P = .041) and aspartate aminotransferase levels (r = .328, P = .009). Conclusions: CHB patients have a significant accumulation of CCL5+ cells in the liver, and CCL5 may play a pathological role in hepatic inflammation of CHB.     

Liver fibrosis on account of chronic hepatitis C is more severe in HIV-positive than HIV-negative patients despite antiretroviral therapy

Summary.  The recent availability of non-invasive tools to measure liver fibrosis has allowed examination of its extent and determination of predictors in all patients with chronic hepatitis C virus (HCV) infection. On the other hand, most information on hepatic fibrosis in HCV/human immunodeficiency virus (HIV)-coinfected patients has been derived from liver biopsies taken before highly active antiretroviral therapy (HAART) was widely available. All consecutive HCV patients with elevated aminotransferases seen during the last 3 years were evaluated and liver fibrosis measured using transient elastography (FibroScan^®) and biochemical indexes. Patients were split according to their HIV serostatus. A total of 656 (69.6%) HCV-monoinfected and 287 (30.4%) HIV/HCV-coinfected patients were assessed. Mean CD4 count of coinfected patients was 493 cells/μL and 88% were under HAART (mean time, 4.2 ± 2.4 years). Advanced liver fibrosis or cirrhosis was recognized in 39% of the coinfected and 18% of the monoinfected patients ( P  < 0.005). A good correlation was found between FibroScan^® and biochemical indexes [AST to platelet ratio index ( r  = 0.405, P  < 0.0001), FIB-4 (r = 0.393, P  < 0.0001) and Forns ( r  = 0.407, P  < 0.0001)], regardless of the HIV status. In the multivariate analysis, age >45 years, body mass index (BMI) >25 kg/m², and HIV infection were independently associated with advanced liver fibrosis or cirrhosis. HIV/HCV-coinfected patients have more advanced liver fibrosis than HCV-monoinfected patients despite the immunologic benefit of HAART.     

Use of simple noninvasive biomarkers to predict liver fibrosis in HIV/HCV coinfection in routine clinical practice

Background

Simple noninvasive tests to predict fibrosis, as an alternative to liver biopsy (LB), are needed. Of these, the aspartate aminotransferase (AST) to platelet ratio index (APRI) and the Forns index (FI) have been validated in HIV/hepatitis C virus (HCV) coinfection. However, these indexes may have lower diagnostic value in situations other than the circumscribed conditions of validation studies. We therefore examined the value of the APRI and FI in HIV/HCV‐coinfected patients for the detection of significant fibrosis in real‐life conditions.

Patients and methods

HIV/HCV‐coinfected patients who had participated in a multicentre cross‐sectional retrospective study were selected if they had undergone an LB within 24 months before the last visit. The predictive accuracy of the APRI and FI was measured using the areas under receiver‐operating‐characteristic curves (AUROCs). Diagnostic accuracy was determined using the positive (PPV) and negative (NPV) predictive values.

Results

A total of 519 coinfected individuals were included in the study. The AUROC [95% confidence interval (95% CI)] of the APRI was 0.67 (0.66–0.71) and that of the FI was 0.67 (0.62–0.71). The PPV of the APRI was 79% and its NPV was 66%. The PPV of the FI was 74% and its NPV was 64%. LB length was available and was ≥15 mm in 120 individuals. In this group, the PPV of the APRI was 85%, and that of the FI was 81%. Using these indexes, 22% of patients could be spared LB. Applying both models sequentially, 30% of patients could be spared LB.

Conclusions

In HIV/HCV‐coinfected patients, the diagnostic accuracy of the APRI in real‐life conditions was similar to that in the validation studies. The FI performed less well. However, combining the two indexes to make decisions on anti‐HCV therapy may prevent a significant proportion of patients from having to undergo LB.     

Persistently normal alanine aminotransferase levels in HIV/HCV-coinfected patients: the role of steatosis

Objective

The frequency and significance of, and liver biopsy findings associated with, a persistently normal alanine aminotransferase (ALT) level in HIV/hepatitis C virus (HCV)‐coinfected patients are poorly characterized. We analysed factors associated with persistently normal ALT levels, defined as at least three consecutive normal ALT values over a 6‐month period, in a group of 381 HIV/HCV‐coinfected patients.

Methods

Patients were categorized into two groups according to ALT values: group 1, patients with persistently normal ALT levels; and group 2, patients with elevated ALT values. Possible interactions with host factors, HIV and HCV viral factors, antiretroviral treatment and histological features were examined.

Results

Thirty‐six patients (9.4%) had persistently normal ALT levels. None of the 36 patients had cirrhosis. Seven patients (19.4%) had a METAVIR fibrosis score of F3. In multivariate analysis, a lower mean METAVIR inflammation score [odds ratio (OR) 0.50, 95% confidence interval (CI) 0.28–0.89; P=0.017], the absence of steatosis (OR 0.43, 95% CI 0.20–0.90; P=0.026) and HCV genotype 4 infection (OR 2.81, 95% CI 1.15–6.68; P=0.023) were associated with persistently normal ALT levels.

Conclusion

The slower progression of chronic hepatitis in patients with persistently normal ALT levels could be related, in part, to a lower frequency of steatosis

     

Food insecurity may lead to incomplete HIV viral suppression and less immune reconstitution among HIV/hepatitis C virus‐coinfected people

Objectives

The aim of this study was to determine the impact of food insecurity (FI) on HIV viral load and CD4 count among people coinfected with HIV and hepatitis C virus (HCV).

Methods

This study was conducted using data from the Food Security & HIV‐HCV Sub‐Study of the Canadian Co‐Infection Cohort study. FI was measured using the adult scale of Health Canada's Household Food Security Survey Module and was classified into three categories: food security, moderate food insecurity and severe food insecurity. The association between FI, HIV viral load, and CD4 count was assessed using a stabilized inverse probability weighted marginal structural model.

Results

A total of 725 HIV/HCV‐coinfected people with 1973 person‐visits over 3 years of follow‐up contributed to this study. At baseline, 23% of participants experienced moderate food insecurity and 34% experienced severe food insecurity. The proportion of people with undetectable HIV viral load was 75% and the median CD4 count was 460 [interquartile range (IQR): 300–665] cells/μL. People experiencing severe food insecurity had 1.47 times [95% confidence interval (CI): 1.14, 1.88] the risk of having detectable HIV viral load and a 0.91‐fold (95% CI: 0.84, 0.98) increase in CD4 count compared with people who were food secure.

Conclusions

These findings provide evidence of the negative impact of food insecurity on HIV viral load and CD4 count among HIV/HCV‐coinfected people.