Nicolás Merchante

Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine.

Background: The hepatotoxicity of highly active antiretroviral therapy (HAART) could enhance liver fibrosis in HIV/Hepatitis C virus (HCV)-coinfected patients. Moreover, HAART-related immune restoration could lessen HCV-associated liver damage. The data on the effect of protease inhibitors (PI) on liver fibrosis are scant and contradictory. No information is available on the relationship between non-nucleoside analogue therapy and liver fibrosis in co-infected patients. Objective: To investigate the associations between the use of different antiretroviral drugs and the liver fibrosis in patients with HIV and HCV infections. Design: Cross-sectional study. Methods: All HIV/HCV co-infected patients with an available liver biopsy and known or estimated duration of HCV infection seen at a Infectious Diseases Unit were included in the study. The fibrosis stage and the fibrosis progression rate were evaluated. Results: The inclusion criteria were fulfilled by 152 patients. Age at HCV infection < 20 years [adjusted odds ratio (AOR), 0.39; 95% confidence interval (CI), 0.19–0.82], PI-based HAART (AOR, 0.39; 95% CI, 0.19–0.78) and nevirapine-based HAART (AOR, 2.56; 95% CI, 1.02–6.58) were associated with fibrosis stage ⩾ F3. The variables associated with fibrosis progression rate > 0.2 units/year were age at HCV infection < 20 years (AOR, 0.23; 95% CI, 0.1–0.52), CD4 cell counts ⩽ 250 × 106/l at liver biopsy (AOR, 2.8; 95% CI, 1.1–7.1), PI-based HAART (AOR, 0.39; 95% CI, 0.2–0.8) and nevirapine-based HAART (AOR, 3.82; 95% CI, 1.9–7.6). Conclusions: HAART regimens including nevirapine are associated with faster liver fibrosis progression in HIV-infected patients with chronic hepatitis C. In contrast, patients on PI as the backbone of potent antiretroviral therapy are more likely to show less liver fibrosis.

High prevalence of hepatitis C virus infection among noninjecting drug users: association with sharing the inhalation implements of crack

Background: Most of the prevalent cases of hepatitis C virus (HCV) infection are attributable to intravenous drug using. However, a substantial number of individuals, particularly noninjecting drug users (NIDU), report no identifiable source of HCV exposure. This may be interpreted as inaccurate reporting of past intravenous exposure or as the presence of an unidentified source of HCV infection. Because of this, we evaluated the prevalence of and factors associated with HCV infection among NIDU.

Benefits From Sustained Virologic Response to Pegylated Interferon Plus Ribavirin in HIV/Hepatitis C Virus–Coinfected Patients With Compensated Cirrhosis

BACKGROUND The objective of this study was to determine the impact of sustained virologic response (SVR) to pegylated interferon (peg-IFN) plus ribavirin (RBV) on the incidence of liver-related complications and overall mortality in human immunodeficiency virus (HIV)-infected patients with compensated hepatitis C virus (HCV)-related cirrhosis. METHODS We included in this prospective cohort study 166 coinfected patients with compensated cirrhosis, who received peg-IFN plus RBV, to assess the time from the starting date of HCV therapy to the first hepatic decompensation and death due to any cause. RESULTS SVR was observed in 43 (25%) individuals. Two (4.6%) patients with SVR developed liver decompensation vs 33 (26.8%) individuals without SVR (P = .002). The incidence of liver-related complications was 0.89 cases per 100 person-years (95% confidence interval [CI], .11-3.1) in SVR patients and 6.4 cases per 100 person-years (95% CI, 4.5-8.9) in non-SVR patients. Factors independently associated with liver decompensation were non-SVR (hazard ratio [HR], 8.1; 95% CI, 1.08-61.5; P = .042) and MELD score ≥9 at baseline (HR, 2.9; 95% CI, 1.2-7.2; P = .016). Two (4.6%) patients with SVR died due to any cause compared with 22 (17.9%) individuals without SVR (P = .02). MELD score ≥9 (HR, 3.1; 95% CI, 1.3-7.7; P = .011) and non-SVR (HR, 8.0; 95% CI, 1.07-61; P = .043) were independently associated with overall mortality. CONCLUSIONS The achievement of SVR following peg-IFN plus RBV markedly reduces the incidence of liver-related decompensation and the overall mortality in HIV/HCV-coinfected patients with compensated cirrhosis.

Natural History of Compensated Hepatitis C Virus-Related Cirrhosis in HIV-Infected Patients

OBJECTIVE To provide information about the incidence and predictors of liver decompensation and death due to liver failure in human immunodeficiency virus (HIV)-infected patients with compensated hepatitis C virus (HCV)-related cirrhosis. METHODS Prospective cohort study of 154 HIV-HCV-coinfected patients with a new diagnosis of Child-Pugh-Turcotte (CPT) class A compensated cirrhosis. We evaluated time from diagnosis to the first liver decompensation and death from liver disease, as well as predictors of these outcomes. RESULTS Thirty-six patients (23.4%) developed liver decompensation. The incidence of liver decompensation was 6.40 cases per 100 person-years (95% confidence interval [CI], 4.18-9.38 cases per 100 person-years). Factors independently associated with liver decompensation were lack of HCV therapy (hazard ratio [HR], 3.38; 95% CI, 1.09-10.53; P = .035), baseline CD4 cell counts <or=300 cells/mm3 (HR, 2.12; 95% CI, 1.14-5.04; P = .021), CPT score 6 versus 5 (HR, 3.33; 95% CI, 1.39-7.69; P = .007), and a diagnosis of cirrhosis based on data other than biopsy or transient elastography (HR, 2.09; 95% CI, 1.05-4.16; P = .036 ). Fifteen patients (9.7%) died; 11 (73%) of these 15 died from liver disease (mortality due to liver failure, 2.44 deaths per 100 person-years; 95% CI, 1.21-4.36 deaths per 100 person-years). Hepatic encephalopathy as the first liver decompensation (HR, 20.67; 95% CI, 2.71-157.57; P = .003), baseline CD4 count <or=300/mm3 (HR, 0.24; 95% CI, 0.07-0.78; P = 0.17), and baseline CPT score 6 (HR, 4.50; 95% CI, 1.63-12.37; P = .004) were independently associated with liver-related death. CONCLUSIONS The incidence of clinical liver events in HIV-HCV-coinfected patients with CPT class A compensated cirrhosis is close to that previously reported in HCV-monoinfected patients. Lower baseline CD4 cell counts, lack of therapy against HCV, and higher CPT score are the factors related to the occurrence of clinical liver events. Minimal changes in CPT score have strong impact in the prognosis of this population.

Liver stiffness predicts clinical outcome in human immunodeficiency virus/hepatitis C virus-coinfected patients with compensated liver cirrhosis†

Our aim was to assess the predictive value of liver stiffness (LS), measured by transient elastography (TE), for clinical outcome in human immunodeficiency virus / hepatitis C virus (HIV/HCV)‐coinfected patients with compensated liver cirrhosis. This was a prospective cohort study of 239 consecutive HIV/HCV‐coinfected patients with a new diagnosis of cirrhosis, done by TE, and no previous decompensation of liver disease. The time from diagnosis to the first liver decompensation and death from liver disease, as well as the predictors of these outcomes, were evaluated. After a median (Q1‐Q3) follow‐up of 20 (9‐34) months, 31 (13%, 95% confidence interval [CI]: 9%‐17%) patients developed a decompensation. The incidence of decompensation was 6.7 cases per 100 person‐years (95% CI, 4.7‐9‐6). Fourteen (8%) out of 181 patients with a baseline LS < 40 kPa developed a decompensation versus 17 (29%) out of 58 with LS ≥ 40 kPa (P = 0.001). Factors independently associated with decompensation were Child‐Turcotte‐Pugh (CTP) class B versus A (hazard ratio [HR] 7.7; 95% CI 3.3‐18.5; P < 0.0001), log‐plasma HCV RNA load (HR 2.1; 95% CI 1.2‐3.6; P = 0.01), hepatitis B virus coinfection (HR, 10.3; 95% CI, 2.1‐50.4; P = 0.004) and baseline LS (HR 1.03; 95% CI 1.01‐1.05; P = 0.02). Fifteen (6%, 95% CI: 3.5%‐9.9%) patients died, 10 of them due to liver disease, and one underwent liver transplantation. CTP class B (HR 16.5; 95% CI 3.4‐68.2; P < 0.0001) and previous exposure to HCV therapy (HR 7.4; 95% CI 1.7‐32.4, P = 0.007) were independently associated with liver‐related death; baseline LS (HR 1.03; 95% CI 0.98‐1.07; P = 0.08) was of borderline significance. Conclusion: LS predicts the development of hepatic decompensations and liver‐related mortality in HIV/HCV‐coinfection with compensated cirrhosis and provides additional prognostic information to that provided by the CTP score. (HEPATOLOGY 2012;56:228–238)

Increasing Incidence of Hepatocellular Carcinoma in HIV-Infected Patients in Spain

BACKGROUND To report the clinical and epidemiological characteristics of hepatocellular carcinoma (HCC) diagnosed in a cohort of human immunodeficiency virus (HIV)-infected patients in Spain. METHODS All HIV-infected patients diagnosed of HCC in 18 hospitals in Spain before 31 December 2010 were included. The main characteristics of HCC cases are described and comparisons between cases according to the year of diagnosis are presented. RESULTS Eighty-two cases of HCC in HIV-infected patients were included, all of them related to viral hepatitis coinfection: hepatitis C virus (HCV) in 66 (81%), hepatitis B virus (HBV) in 6 (7%), and HBV/HCV in 10 (12%). From 1999, when the first case of HCC was diagnosed, a progressive increment in the incidence of HCC in the cohort has occurred. In patients coinfected with HIV/HCV-coinfected patients, the incidence HCC increased from 0.2 to 2.8 cases per 1000 person-years between 2000 and 2009. Death occurred in 65 patients (79%), with a median survival of 91 days (interquartile range, 31-227 days). Three of 11 patients (28%) who received potentially curative therapy died, compared with 62 of 71 patients (87%) who did not receive curative therapy (P = .0001). Compared with cases of HCC diagnosed before 2005, cases diagnosed later did not show a higher survival rate. CONCLUSIONS HCC is an emerging complication of cirrhosis in HIV-infected patients. A sharp increase in its incidence has occurred in those also infected by HCV in the recent years. Unfortunately, HCC is frequently diagnosed at an advanced stage, and mortality continues to be very high, with no significant changes in recent years. Earlier diagnosis, which may allow potentially curative therapy, is necessary.

Insulin resistance is associated with liver stiffness in HIV/HCV co-infected patients

Background: The factors that influence liver fibrosis progression in patients co-infected with human immunodeficiency virus/hepatitis C virus (HIV/HCV) are not completely understood. It is not known if insulin resistance (IR), a condition that promotes liver fibrosis in HCV mono-infected individuals, is one of these factors. Objective: To evaluate the association between IR and liver stiffness (LS). Design: Multicentre cross-sectional study. Patients: 330 patients co-infected with HIV/HCV. Methods: LS was assessed by transient elastography, which has shown a high accuracy to predict significant fibrosis in patients co-infected with HIV/HCV. The outcome variable of the study was LS. Patients with LS⩾9 kPa were considered as having significant fibrosis. IR was calculated using the HOMA method. Results: LS was ⩾9 kPa in 150 (45%) patients. HOMA correlated with LS (Spearman’s rho correlation coefficient, 0.37; p<0.0001). The median (Q1–Q3) HOMA in patients with LS⩾9 kPa was 3.30 (2.17–5.16) while it was 2.09 (1.37–3.22) in patients with LS <9 kPa (p<0.0001). Ninety-six (39%) individuals with a HOMA <4 and 54 (63%) with a HOMA ⩾4 showed LS⩾9 kPa (p<0.0001). Analyses after excluding patients with cirrhosis yielded similar results. After multivariate analyses, age ⩾40 years (adjusted odds ratio (AOR), 1.85; 95% confidence interval (CI), 1.03 to 3.29; p = 0.03), CD4 cell count <200 cells/ml (AOR, 3.45; 95% CI, 1.67 to 7.11; p = 0.001), hepatitis B virus co-infection (AOR, 9.25; 95% CI, 2.42 to 35.31; p = 0.001), and HOMA ⩾4 (AOR, 5.33; 95% CI, 2.70 to 10.49; p<0.0001) were the independent predictors of LS⩾9 kPa. Conclusion: IR is associated with LS in patients co-infected with HIV/HCV.

Prevalence and risk factors for abnormal liver stiffness in HIV-infected patients without viral hepatitis coinfection: role of didanosine.

BACKGROUND Unexpected cases of severe liver disease in HIV-infected patients have been reported and an association with didanosine (ddI) has been suggested. Transient elastography (TE) might detect patients harbouring such a condition. Our objective was to search for the presence of abnormal liver stiffness (LS) in a cohort of HIV-infected patients without HBV or HCV coinfection and to assess the related factors. METHODS A cross-sectional prospective study was conducted. LS was assessed by TE in 258 HIV-infected patients without HBV or HCV coinfection and with no evidence of acute hepatotoxicity or other origins of liver disease. LS values > or =7.2 kPa were considered abnormal. Multivariate analyses were performed to identify factors associated with abnormal LS. RESULTS Abnormal LS was observed in 29 (11.2%) patients. A total of 18 (16.4%) patients previously treated with ddI and 11 (7.4%) of those who never received ddI had LS values > or =7.2 kPa (P=0.02). The prevalence of abnormal LS was higher in patients previously treated with abacavir than in those who had never received abacavir (15 [21.7%] versus 14 [7.4%]; P=0.001). After multivariate analyses, age (adjusted odds ratio [AOR] 1.05, 95% confidence interval [CI] 1.002-1.1; P=0.004) alcohol intake >50 g/day (AOR 7.2, 95% CI 2.6-19.7; P<0.0001), CD4(+) T-cell count <200 cells/ml (AOR 3.4, 95% CI 1.06-11.007; P=0.03), time on ddI treatment (AOR 1.31, 95% CI 1.12-1.52; P=0.001) and previous abacavir exposure (AOR 3.01, 95% CI 1.18-7.67; P=0.02) were independently associated with abnormal LS. CONCLUSIONS The prevalence of abnormal LS in HIV-infected patients without HBV or HCV coinfection is substantial. Long-term exposure to ddI is a major cause of liver damage in these patients.

Increased Hepatocyte Fas Expression and Apoptosis in HIV and Hepatitis C Virus Coinfection

BACKGROUND Chronic hepatitis C disease (CHC) follows an accelerated course in human immunodeficiency virus (HIV) coinfection. The reasons for this are unclear. Fas-mediated hepatocyte apoptosis is involved in the pathogenesis of hepatitis C virus (HCV) infection. We sought to compare the expression of Fas on hepatocytes and irreversible apoptosis of hepatocytes among patients with CHC with and without HCV/HIV coinfection. METHODS Fas-immunostained hepatocytes were semiquantified, and apoptotic hepatocytes were detected by staining caspase-cleaved cytokeratin 18 filaments and counted across the entire section of liver-biopsy specimens from HCV-infected patients with and without HCV/HIV coinfection. RESULTS One hundred thirty-four HCV/HIV-coinfected and 100 HCV-infected patients were included. HCV/HIV coinfection was associated with both diffuse distribution of Fas-stained hepatocytes (adjusted odds ratio [AOR], 7.4 [95% confidence interval {CI}, 3.8-14.4]) and with apoptotic hepatocyte counts greater than the median (AOR, 2.5 [95% CI, 1.5-4.5]). In HCV/HIV-coinfected patients, CD4+ cell nadir<200 cells/mL was associated with both Fas expression (AOR, 2.9 [95% CI, 1.3-6.8]) and hepatocyte apoptosis (AOR, 2.3 [95% CI, 1.1-4.9]). CONCLUSION HCV/HIV-coinfected patients show higher levels of hepatocytes expressing Fas and undergoing irreversible apoptosis than do HCV-infected patients. However, low CD4+ cell nadirs in coinfected patients are associated with hepatocyte Fas expression and apoptosis.

Hepatic steatosis and steatohepatitis in human immunodeficiency virus/hepatitis C virus-coinfected patients.

Hepatic steatosis (HS) is frequent in human immunodeficiency virus (HIV)‐ and hepatitis C virus (HCV)‐coinfected patients. Antiretroviral therapy (ART) and metabolic alterations could induce HS. However, a protective effect of ART has been reported in a paired biopsy study. Thus, our aim was to examine the changes and predictors of HS progression among HIV/HCV‐coinfected patients with sequential biopsies. We also evaluated the rates of steatohepatitis and factors associated thereof. HIV‐infected patients with detectable serum HCV RNA, who underwent two biopsies, separated at least by 1 year, were included in this retrospective study. HS progression was defined as increase in one or more HS grades. The median (interquartile range) time between biopsies was 3.3 (2.0‐5.2) years. Among 146 individuals, HS at baseline was observed in 86 (60%) patients and in 113 (77%) in the follow‐up biopsy (P < 0.001). Progression of HS was observed in 60 (40%) patients. HS regressed in 11 (8%) patients. Factors associated with HS progression were changes in fasting plasma glucose (FPG) between biopsies (per 10 mg/dL increase; odds ratio [OR] [95% confidence interval; CI] = 1.4 [1.04‐1.8]; P = 0.024) and cumulative use of dideoxynucleoside analogs (per year; OR [95% CI] = 1.5 [1.2‐1.8]; P = 0.001). Persistent steatohepatitis or progression to steatohepatitis between biopsies was observed in 27 (18%) patients. Persistence of or progression to steatohepatitis was associated with progression ≥1 fibrosis stages between biopsies (OR [95% CI] = 2.4 [1.01‐5.7]; P = 0.047). Conclusions: HS progresses frequently and regression is rarely observed in HIV/HCV‐coinfected patients, including in those on ART. Cumulative exposure to dideoxynucleoside analogs and increases in FPG are related with HS progression. Stetatohepatitis is frequently observed in these patients and is linked to fibrosis progression. (HEPATOLOGY 2012)