Liver fibrosis in patients with chronic hepatitis C and persistently normal liver enzymes: influence of HIV infection

Summary. Liver fibrosis progress slowly in patients with chronic hepatitis C and persistently normal alanine aminotransferase (PNALT) compared to subjects with elevated aminotransferases. Differences in liver fibrosis according to human immunodeficiency virus (HIV) status in this population have not been examined. All patients with serum hepatitis C virus (HCV)‐RNA and PNALT who underwent liver fibrosis assessment using elastometry since 2004 at three different European hospitals were evaluated. Patients previously treated with interferon were excluded. PNALT was defined as ALT below the upper limit of normality in at least three consecutive determinations within the last 12 months. Fibrosis stage was defined as mild (Metavir F0–F1) if stiffness ≤7.1 kPa; moderate (F2) if 7.2–9.4 kPa; severe (F3) if 9.5–14 kPa, and cirrhosis (F4) if >14 kPa. A total of 449 HIV‐negative and 133 HIV‐positive patients were evaluated. HIV‐negative patients were older (mean age 51.8 vs 43.5 years) and more frequently females (63%vs 37%) than the HIV counterparts. Mean serum HCV‐RNA was similar in both the groups (5.9 vs 5.8 log IU/mL). Overall, 78.8% of the HIV patients were on HAART and their mean CD4 count was 525 (±278) cells/μL. In HIV‐negatives, liver fibrosis was mild in 84.6%; moderate in 8.7%, severe in 3.3% and cirrhosis was found in 3.3%. In HIV patients, these figures were 70.7%, 18.8%, 6%, and 4.5%, respectively. In the multivariate logistic regression analysis, older age (odds ratio or OR: 1.04; 95% confidence interval or CI: 1.02–1.07; P < 0.001) and being HIV+ (OR: 2.6; 95% CI: 1.21–5.85; P < 0.01) were associated with severe liver fibrosis or cirrhosis (F3–F4). Thus, severe liver fibrosis and cirrhosis are seen in 6.6% of the HCV‐monoinfected and in 10.5% of HCV‐HIV co‐infected patients with PNALT. Some degree of liver fibrosis that justifies treatment is seen in 15% of the HCV‐monoinfected but doubles to nearly 30% in HIV‐HCV co‐infected patients with PNALT.     

Treatment of chronic hepatitis C in HIV‐infected patients with compensated liver cirrhosis

Summary. The greatest benefit of hepatitis C virus (HCV) therapy is seen in cirrhotics attaining sustained virological response (SVR). However, concerns about toxicity and poorer responses often discourage treatment of cirrhotics. This may be particularly relevant in HIV–HCV‐coinfected patients, in whom progression of liver fibrosis is faster and treatment responses lower. This is a retrospective analysis of HIV–HCV‐coinfected patients who had received peginterferon–ribavirin therapy at our institution. Individuals naïve for interferon in whom liver fibrosis had been assessed using elastometry within the year before being treated were chosen. Response rates and toxicities were compared in cirrhotics (>14.5 KPa) and noncirrhotics. Patients with previous liver decompensation were excluded. Overall, 41 cirrhotics and 190 noncirrhotics entered the study. Groups were similar in age, gender, HCV genotypes and baseline serum HCV‐RNA. SVR occurred at similar rates in cirrhotic and noncirrhotics, either considered by intention‐to‐treat (39%vs 45%; P = 0.4) or as treated (50%vs 52%, P = 0.8). In multivariate analysis (odds ratio, 95% CI, P), SVR was associated with HCV genotypes 2–3 (5, 2.9–11, <0.01) and lower serum HCV‐RNA (2, 1.4–3.03 for every log decrease, <0.01) but not with cirrhosis (1.2, 0.4–3.6, 0.6). Treatment discontinuations because of adverse events tended to be more common in cirrhotics than in noncirrhotics (17%vs 12%; P = 0.2), but only severe thrombocytopenia was more frequent in cirrhotics than in non‐cirrhotics (20%vs 3% at week 24; P < 0.01). Response to peginterferon–ribavirin therapy is similar in HIV–HCV coinfected patients with and without liver cirrhosis. Therefore, treatment must be encouraged in all compensated cirrhotic patients, although closer monitoring and management of side effects, mainly thrombocytopenia, may be warranted.     

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.     

Prevalence and factors associated with significant liver fibrosis assessed by transient elastometry in HIV/hepatitis C virus‐coinfected patients

Summary. Transient elastometry (TE) could provide a more accurate evaluation of the frequency and risk factors of liver fibrosis in hepatitis C virus (HCV) infection than that based on biopsy. The aim of this study was to assess the prevalence of and factors associated with significant liver fibrosis in a large population of HIV/HCV‐coinfected patients. HIV/HCV‐coinfected patients, who had participated in a cross‐sectional, multicenter, retrospective study of liver fibrosis using noninvasive markers and in whom a determination of liver stiffness (LS) by TE was available, were included in this analysis. Factors potentially associated with significant fibrosis (LS ≥ 9 kPa) were analyzed. One thousand three hundred and ten patients fulfilled the inclusion criteria, 526 (40%) of them showed LS ≥ 9 kPa and 316 (24%) cirrhosis (LS ≥ 14 kPa). The factors independently associated with significant fibrosis [adjusted odds ratio (95% confidence interval, P value) were the following: older age [1.04 (1.01–1.07), 0.002], daily alcohol intake > 50 g/day [1.58 (1.10–2.27), 0.013] and the length of HCV infection [1.03 (1.00–1.06), 0.023]]. A CD4 cell count lower than < 200 per mm³ [1.67 (0.99–2.81), 0.053] and HCV genotype 4 [0.66 (0.42–1.02), 0.066] were marginally associated with LS ≥ 9 kPa. In conclusion, the prevalence of cirrhosis in HIV/HCV‐coinfected patients seems to be higher than previously reported in studies based on liver biopsy. Older age, alcohol consumption and lower CD4 cell counts are related with significant fibrosis. The latter association supports an earlier starting of antiretroviral therapy in this setting.     

Response to pegylated interferon plus ribavirin in HIV-infected patients with chronic hepatitis C due to genotype 4

SUMMARY: Hepatitis C virus (HCV) genotypes 1 and 4 respond less well to pegylated interferon (pegIFN) plus ribavirin (RBV) therapy. For this reason most studies merge these two genotypes when assessing virological response. However, in most trials the HCV genotype 4 population is rather small, and conclusions are mainly derived from what occurs in HCV-1 patients. All HCV-4 patients coinfected with HIV who received pegIFN plus RBV in two different multicentre studies, PRESCO and ROMANCE, conducted respectively in Spain and Italy, were retrospectively analyzed. Baseline plasma HCV-RNA, proportion of patients with HCV-RNA <10 IU / mL at week 4 (rapid virological response), and HCV-RNA declines >2 logs at week 12 (early virological response, EVR) were all assessed as predictors of sustained virological response (SVR). Overall, 75 patients (60 men) were evaluated. Median age was 40 years and median CD4 count 598 cells / mm(3); 49% had plasma HIV-RNA <50 copies / mL; 71% had elevated liver enzymes and 31% had advanced liver fibrosis (Metavir F3-F4). Median serum HCV-RNA was 5.7 log IU / mL. Rapid virological response was attained by 10 (20%) patients and EVR by 26 (42%). Using intention-to-treat and on-treatment (OT) analyses, SVR was achieved by 21 / 75 (28%) and 21 / 62 (34%) of HCV-4 patients, respectively. In the multivariate analysis (OT), baseline HCV-RNA (OR 0.09 for every log increment; 95% CI: 0.01-0.7) and EVR (OR: 7.08; 95% CI: 1.8-27.2) were significantly and independently associated with SVR. This is the largest series of HIV-infected patients with chronic hepatitis C due to HCV-4 treated with pegIFN plus RBV examined so far and the results show that HCV-4 behaves similarly to HCV-1. Therefore, these patients should be considered as difficult to treat population. Baseline serum HCV-RNA and EVR are the best predictors of SVR in HCV-4 / HIV-coinfected patients.     

Impact of liver steatosis on the correlation between liver stiffness and fibrosis measured by transient elastography in patients coinfected with human immunodeficiency virus and hepatitis C virus

Summary. We assessed the effect of different hepatic conditions such as fibrosis, steatosis and necroinflammatory activity on liver stiffness as measured by transient elastography in HIV/HCV‐coinfected patients. We studied all consecutive HIV/HCV‐coinfected patients who underwent liver biopsy and elastography between January 2007 and December 2008. Liver fibrosis was staged following METAVIR Cooperative Study Group criteria. Steatosis was categorized according to the percentage of affected hepatocytes as low (≤10%), moderate (<25%) and severe (≥25%). A total of 110 patients were included. Fibrosis was distributed by stage as follows: F0, n = 13; F1, n = 47; F2, n = 29; F3, n = 18; and F4, n = 3. Liver biopsy revealed the presence of hepatic steatosis in 68 patients (low to moderate, n = 53; and severe n = 15). By univariate regression analysis, fibrosis, necroinflammatory activity, and the degree of steatosis were correlated with liver stiffness. However, in a multiple regression analysis, steatosis and fibrosis were the only independent variables significantly associated with liver stiffness. With a cut‐off of 9.5 kPa to distinguish patients with F ≤ 2 from F ≥ 3, elastography led to a significantly higher number of misclassification errors (25%vs 5%; P = 0.014), most of which were false positives for F ≥ 3. Our study suggests that the correlation between liver stiffness and fibrosis as estimated by transient elastography may be affected by the presence of hepatic steatosis in HIV/HCV‐coinfected patients.     

Optimized threshold for serum HCV RNA to predict treatment outcomes in hepatitis C patients receiving peginterferon alfa‐2a/ribavirin

Summary. It is unclear whether the current threshold for ‘high’ hepatitis C virus (HCV) RNA level (800 000 IU/mL) is optimal for predicting sustained virological response (SVR). We retrospectively analysed pretreatment HCV RNA levels and SVR rates in 1529 mono‐infected and 176 HIV–HCV co‐infected patients treated with peginterferon alfa‐2a (40 kD) plus ribavirin. We improved the threshold for differentiating low and high viral load by fitting semiparametric generalized additive logistic regression models to the data and constructing receiver operating characteristics curves. Among HCV genotype 1 mono‐infected patients, the difference in SVR rates between those with low and high baseline HCV RNA levels was 27% (70%vs 43%) when 400 000 IU/mL was used and 16% (59%vs 43%) when 800 000 IU/mL was used. In HIV–HCV genotype 1 co‐infected patients, the difference was 51% (71%vs 20%) when 400 000 IU/mL was used and 43% (61%vs 18%) when 800 000 IU/mL was used. A lower threshold (200 000 IU/mL) was identified for genotype 1 mono‐infected patients with ‘normal’ alanine aminotransferase (ALT) levels. No threshold could be identified in HCV genotype 2 or 3 patients. A threshold HCV RNA level of 400 000 IU/mL is optimal for differentiating high and low probability of SVR in genotype 1‐infected individuals with elevated ALT.     

Hepatitis C virus NS3/4A quasispecies diversity in acute hepatitis C infection in HIV‐1 co‐infected patients

The growing number of cases of acute hepatitis C (AHC) infections among human immunodeficiency virus type 1 (HIV‐1)‐positive men who have sex with men (MSM) in the last 10 years has promoted the search for predictors of AHC clearance as well as for epidemiological networks of viral transmission. We characterized the diversity and catalytic efficiency of HCV NS3/4A protease quasispecies in AHC patients coinfected with HIV‐1. Plasma samples obtained at HCV diagnosis from 18 MSM HIV‐coinfected patients with AHC were studied. Five HCV monoinfected patient samples with AHC were also investigated. An average of 39 clones from each sample was analysed. The catalytic efficiency of the dominant quasispecies (i.e. the most abundant) from each quasispecies was also assayed for mitochondrial antiviral signalling protein (MAVS) cleavage. Phylogenetic analysis identified two clusters of patients with highly related viruses, suggesting a common source of HCV infection. None of the 18 MSM HIV‐coinfected patients spontaneously cleared HCV, although 78% of the treated patients achieved a sustained virological response after early treatment with pegylated interferon (pegIFN) plus ribavirin (RBV). The synonymous‐nonsynonymous (ds/dn) mutation ratio, a marker of selective pressure, was higher in AHC compared to 26 HIV‐1‐infected men with genotype 1a chronic hepatitis C (CHC) (P < 0.0001). NS3/4A proteases from AHC patients also exhibited higher catalytic efficiency compared to CHC patients (P < 0.0001). No differences were found when ds/dn mutation ratios and NS3/4A protease catalytic efficiencies from AHC HIV‐coinfected patients were compared with AHC monoinfected patients. The presence of epidemiological networks of HCV transmission was confirmed among HIV‐1‐positive MSM. In addition, substantial genetic diversity was demonstrated in AHC. NS3/4A protease efficiency cleaving MAVS may be associated with virus transmission and response to pegIFN/RBV treatment.     

Regression of liver fibrosis is progressive after sustained virological response to HCV therapy in patients with hepatitis C and HIV coinfection

There are few data about the long‐term histological outcome of HIV‐/HCV‐coinfected patients after therapy with interferon and ribavirin. We performed an observational study of 216 patients who received therapy against HCV and who had at least three successive transient elastographies (TE) during the follow‐up. The primary endpoint was confirmed fibrosis regression, defined as a reduction of at least 1 point in Metavir fibrosis score, confirmed and without worsening in successive TE. At baseline, 23% had fibrosis stage 4 or cirrhosis. Overall, 82 (38%) achieved sustained virological response (SVR), without differences in baseline fibrosis or time of follow‐up. Confirmed fibrosis regression was observed in 55% of patients, higher for SVR (71% vs 44%; P < 0.01), and the likelihood of achieving fibrosis regression at 3, 5 and 7 years was 0.17, 0.51 and 0.67, respectively, for SVR patients, in comparison with 0.02, 0.23 and 0.41 for no SVR patients (P < 0.01, log‐rank test at any time point). Progressive regression, defined as continuous improvement in successive TE, was observed in 62% of patients with advanced liver fibrosis or cirrhosis who achieved SVR. In a Cox regression model, only SVR (HR, 4.01; 95% CI, 2.33–7.57; P < 0.01) and a younger age (HR, 1.14; 95% CI, 1.05–1.25; P < 0.01; per year) were associated with fibrosis regression. This study confirms that the rate of liver fibrosis regression increases during the follow‐up after SVR to interferon therapy in HIV‐/HCV‐coinfected patients.     

Impact of HIV on liver fibrosis in men with hepatitis C infection and haemophilia

Summary. Hepatitis C virus (HCV) is the major cause of liver disease in haemophilia. Few data exist on the proportion with liver fibrosis in this group after long‐term HCV and HIV co‐infection. We conducted a cross‐sectional multi‐centre study to determine the impact of HIV on the prevalence and risk factors for fibrosis in haemophilic men with chronic hepatitis C. Biopsies were independently scored by Ishak, Metavir and Knodell systems. Variables were tested for associations with fibrosis using logistic regression and receiver operating curves (ROC). Of 220 biopsied HCV(+) men, 23.6% had Metavir ≥F3 fibrosis, with higher mean Metavir fibrosis scores among HIV/HCV co‐infected than HCV mono‐infected, 1.6 vs. 1.3 (P = 0.044). Variables significantly associated with fibrosis included AST, ALT, APRI score (AST/ULN × 100/platelet × 10⁹/L), alpha‐fetoprotein (all P < 0.0001), platelets (P = 0.0003) and ferritin (P = 0.0008). In multiple logistic regression of serum markers, alpha‐fetoprotein, APRI and ALT were significantly associated with ≥F3 fibrosis [AUROC = 0.77 (95% CI 0.69, 0.86)]. Alpha‐fetoprotein, APRI and ferritin were significant in HIV(?) [AUROC = 0.82 (95% CI 0.72, 0.92)], and alpha‐fetoprotein and platelets in HIV(+) [AUROC = 0.77 (95% CI 0.65, 0.88]. In a multivariable model of demographic and clinical variables, transformed (natural logarithm) of alpha‐fetoprotein (P = 0.0003), age (P = 0.006) and HCV treatment (P = 0.027) were significantly associated with fibrosis. Nearly one‐fourth of haemophilic men have Metavir ≥3 fibrosis. The odds for developing fibrosis are increased in those with elevated alpha‐fetoprotein, increasing age and past HCV treatment.     

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.     

A randomized,placebo‐controlled study of the NS5B inhibitor beclabuvir with peginterferon/ribavirin for HCV genotype 1

Beclabuvir is a potent, non‐nucleoside inhibitor of the HCV NS5B RNA polymerase, with nanomolar activity against HCV genotypes 1, 3, 4, 5 and 6 in vitro. This study evaluated the efficacy and safety of beclabuvir, in combination with peginterferon alfa‐2a (pegIFN) and ribavirin (RBV), in HCV genotype 1. In this randomized (1:1:1), double‐blinded, placebo‐controlled, dose‐ranging phase 2a study, 39 treatment‐naive patients chronically infected with HCV genotype 1 were treated for 48 weeks with beclabuvir (75 mg or 150 mg) plus pegIFN (180 μg) and RBV (1000 mg/day [<75 kg] or 1200 mg/day [≥75 kg]) vs pegIFN/RBV alone. The primary efficacy endpoint of extended rapid virologic response (undetectable HCV RNA at treatment weeks 4 and 12) was achieved by 76.9% (10/13) of patients receiving beclabuvir 75 mg and 38.5% (5/13) receiving beclabuvir 150 mg vs 0% receiving pegIFN/RBV alone. Higher response rates were observed among patients receiving beclabuvir 75 mg for all secondary efficacy endpoints, including sustained virologic response at follow‐up weeks 12 or 24. Three patients experienced virologic breakthrough on treatment, all in the beclabuvir 150‐mg treatment group. Beclabuvir was well tolerated at both doses, with the most commonly observed adverse events (headache, fatigue, nausea, decreased appetite, irritability, depression and insomnia) consistent with those observed with pegIFN/RBV. In conclusion, beclabuvir was both effective and well tolerated when administered in combination with pegIFN/RBV for the treatment of chronic HCV GT 1, supporting the study of beclabuvir as part of an all‐oral regimen for HCV GT1.     

Serum bile acid levels as a predictor for the severity of liver fibrosis in patients with chronic hepatitis C

Summary. Serum bile acids (SBAs) are commonly elevated in cholestatic liver diseases, but it is unclear if SBA levels are also elevated in noncholestatic chronic liver diseases and whether those levels correlate with disease severity. We analysed SBA levels of 135 consecutive patients with chronic hepatitis C virus infection and correlated these levels with the degree of liver fibrosis as determined by liver biopsy. In addition, we assessed the accuracy of SBA levels as a noninvasive predictor for liver fibrosis by its comparison to the patients’ FibroTest scores. Two‐thirds (90/135 patients, 67%) of the study patients had nonsevere liver fibrosis (Metavir F0–F2), and the others (45/135, 33%) had severe fibrosis or cirrhosis (Metavir F3–F4). The SBA levels were significantly higher in patients with severe fibrosis as compared to nonsevere fibrosis (11.46 ± 10.01 vs 6.37 ± 4.69, P < 0.0001). Furthermore, a receiver operator characteristics curve based on a model that included serum bile acids, age, body mass index, serum AST, glucose and cholesterol levels suggested that this combination reliably predicts the degree of liver fibrosis and is not inferior to the current noninvasive FibroTest score (areas under the curve of 0.837 vs 0.83, respectively, P = 0.87). We conclude that measurement of SBA levels may have a clinical role as a simple noninvasive tool to assess the severity of HCV‐induced liver disease. Combined with widely available laboratory parameters, SBA levels can predict disease severity with a high degree of accuracy.     

Discriminant value of serum HBV DNA levels as predictors of liver fibrosis in chronic hepatitis B

Summary. Current guidelines recommend antiviral therapy in chronic hepatitis B (HBV) patients with significant histological disease. We aimed to compare histological fibrosis (METAVIR, ≥F2) in patients with HBV DNA ≥20 000 IU/mL vs≥2000 IU/mL and identify predictors of fibrosis. We performed prospective liver biopsies on 203 HBeAg‐negative patients in four groups: Group I (n = 55): HBV DNA ≥20 000 IU/mL and persistently elevated alanine aminotransferase (ALT) levels (PEALT; >40 U/L); Group II (n = 34): HBV DNA ≥20 000 IU/mL and persistently normal ALT (PNALT); Group III (n = 40): HBV DNA <20 000 IU/mL and PEALT; and Group IV (n = 74): HBV DNA <20 000 IU/mL, and PNALT. We reanalysed all groups in relation to updated cut‐off for treatable viremia (2000 IU/mL). Genotype D was detected in 86% of patients. Hepatic fibrosis ≥F2 was detected in 72.7%, 52.9%, 57.5% and 18.9% in Groups I–IV, respectively (P < 0.0001). Except in Group II with a trend for lower ≥F2 fibrosis (P = 0.067), there was no significant difference by using HBV DNA cut‐off 20 000 vs 2000 IU/mL. Multivariate logistic regression analysis identified study Group IV (OR, 0.0276; CI: 0.088–0.868; P = 0.0276) and milder (A0–1) necroinflammatory grade (OR, 0.135; CI: 0.063–0.287; P < 0.0001) as independent predictors of ≥F2 fibrosis. The specificity, positive and negative predictive values for PEALT in detection of ≥F2 fibrosis for viremia ≥2000 IU/mL (80%, 69% and 65%, respectively) or ≥20 000 IU/mL (86%, 73% and 63%, respectively) were similar, with a marginal gain in sensitivity (51%vs 42%, respectively). Significant fibrosis is prevalent in a large proportion of HBeAg‐negative patients with high viremia and persistently normal ALT. Lower HBV DNA cut‐offs could be adopted with marginal gains in fibrosis detection and without loss of diagnostic accuracy.     

Prevalence and clinical significance of GB virus type C/hepatitis G virus coinfection in patients with chronic hepatitis C undergoing antiviral therapy

Summary. Coinfection with GBV‐C/HGV in patients with chronic hepatitis C (CHC) may influence clinical course and response rates of antiviral therapy. Aim of the study was to investigate the prevalence of GBV‐C/HGV/HCV coinfection and its influence on outcome of interferon/ribavirin combination therapy. Three hundred and four patients with CHC [m/f = 211/93, age: 42 (18–65)] were investigated. HGV RNA detection was performed by polymerase chain reaction prior to and 6 months after the end of antiviral therapy. HGV/HCV coinfection could be identified in 37/304 (12.2%) patients with intravenous drug abuse as the most common source of infection (N = 21, (56.8%)). The predominant HCV genotype in coinfected individuals was HCV‐3a (HCV‐3a: 51.4%, HCV‐1: 37.8%, HCV‐4: 10.8%). HGV coinfection was more prevalent in patients infected with HCV‐3 compared to HCV‐1 or HCV‐4 [19/45 (42.2%) vs 14/185 (7.6%) vs 4/52 (7.7%), P < 0.01]. Patients with HGV/HCV coinfection were younger [35 (18–56) vs 43 (19–65), years; P < 0.01], and advanced fibrosis (F3‐F4) was less frequent (22.2%vs 42.9%, P < 0.05). A sustained virological response was achieved more frequently in HGV/HCV coinfected patients [26/37 (70.3%)] than in monoinfected patients [120/267 (44.9%), P < 0.01]. HGV RNA was undetectable in 65.7% of the coinfected patients at the end of follow‐up. Intravenous drug abuse seems to be a major risk factor for HGV coinfection in patients with chronic hepatitis C. Coinfection with HGV does not worsen the clinical course of chronic hepatitis C or diminish response of HCV to antiviral therapy. Interferon/ribavirin combination therapy also clears HGV infection in a high proportion of cases.     

Is serum alanine transaminase level a reliable marker of histological disease in chronic hepatitis C infection?

Background: Approximately 20–30% of patients chronically infected with hepatitis C virus (HCV) have persistently normal alanine transaminase (PNALT) levels. These patients are described to have a mild degree of histological liver damage. We aimed to assess the histological liver changes in HCV patients with PNALT. Patients and methods: Sixty‐five patients with HCV and PNALT (group A) underwent a liver biopsy. PNALT was defined as three or more determinations identified to be within the normal range over 6 months or longer. The demographical features and histological changes were compared with 66 consecutive patients with chronic HCV infection and elevated ALT (group B). All patients had a detectable HCV RNA. Histological disease was scored according to the METAVIR system. Results: Females were more likely to have normal ALT levels (65%). The mean ALT level in Group A and B was 30 and 105 IU/L respectively. No patient in either group had normal histology. The mean necro‐inflammatory scores in groups A and B (2.0±0.68 vs 2.09±0.67) and the mean fibrosis scores (2.11±0.87 vs 2.24±1.04) were not significantly different. Bridging fibrosis in groups A and B was seen in 24.6 and 37.9% patients, respectively, while cirrhosis was seen in 6.2 and 7.6% patients respectively. Hepatic steatosis in groups A and B (0.94±0.86 vs 1.0±1.02 respectively) was also not significantly different and did not show any association with the fibrosis scores across the two groups. In group A, the necro‐inflammatory and fibrosis scores of patients with and without steatosis were not statistically significant. Age was the only predictor of normal ALT levels. However, increasing age did not show a significant increase in histological activity in either group beyond a certain age. Conclusion: This study demonstrates that ALT is a poor surrogate marker for inflammation and fibrosis in HCV patients. Given the presence of significant necro‐inflammation in PNALT patients, the risk/benefit ratio justifies treatment without the need for a liver biopsy.     

Viral kinetics and early prediction of nonresponse to peg-IFN-alpha-2b plus ribavirin in HCV genotypes 1/4 according to HIV serostatus

Summary. To evaluate, among 70 hepatitis C virus (HCV)‐monoinfected and 36 human immunodeficiency virus (HIV)‐coinfected naïve patients with genotypes 1/4 receiving weight‐adjusted pegylated interferon‐α‐2b/ribavirin, viral kinetics and the feasibility to predict treatment failure measuring early HCV‐RNA decreases. HCV‐RNA was assessed at baseline, weeks 4, 12 and 24. Receiver operating characteristic (ROC) curves were calculated to determine the most sensitive cut‐off values of viral decrease at week 4 predicting treatment failure. Baseline predictors of failure were evaluated by univariate and multivariate analyses. Despite similar baseline HCV‐RNA (5·75 vs 5·72 log₁₀IU/ml, P = 0·6), HCV monoinfection led to significantly lower HCV‐RNA values at weeks 4 (3·7 vs 4·3 log₁₀IU/ml, P = 0·01), 12 (2·3 vs 3·5 log₁₀IU/ml, P = 0·01) and 24 (1·4 vs 3·3 log₁₀IU/ml, P = 0·001) and a higher rates of viral clearance at weeks 24 (60%vs 36%, P = 0·02), 48 (46%vs 25%, P = 0.03) and 72 (37%vs 17%). The lack of achieving an HCV‐RNA decrease of at least 1 log₁₀ at week 4 was highly predictive of treatment failure for HCV‐monoinfected patients (Se 100%, Sp 50%, positive predictive value (PPV) 57%, negative predictive value (NPV) 100%, ROC curve area, 0·86 [95% confidence interval (CI) 0·77–0·95], but not for HCV/HIV‐coinfected patients (cut‐off, 0 log₁₀, Se 100%, Sp 27%, PPV 21%, NPV 100%, ROC curve area, 0·71 (95% CI 0·49–0·93). HIV coinfection was independently associated with failure (odds ratio 2.95, 95% CI 1·08–8.04, P = 0·01). Thus the magnitude of HCV‐RNA decreases at week 4 correlated with treatment response. Significant differences in viral kinetics and cut‐off values predicting nonresponse suggest a slower HCV clearance rate in HIV coinfection, which was independently associated with treatment failure.     

Ribavirin suppresses erythroid differentiation and proliferation in chronic hepatitis C patients

Combination therapy with pegylated interferon (pegIFN) plus ribavirin (RBV) is the standard of care for chronic hepatitis C. One of the major treatment‐related side effects is anaemia, attributed to RBV‐induced haemolysis. However, haemolysis biomarkers are not present in all patients supporting the existence of other pathogenetic mechanisms. We studied the role of RBV in inducing haemolysis and its effects on erythropoiesis. In 18 hepatitis C virus (HCV) genotype 2 patients treated with pegIFN‐alpha‐2a (180 mcg/week) plus RBV (800 mg/day) for 24 weeks and in 10 hepatitis B virus (HBV) patients treated with pegIFN‐alpha‐2a (180 mcg/week) for 48 weeks, haemolysis was assessed by serum LDH, haptoglobin and reticulocyte count. Erythropoiesis was evaluated both ex vivo, analysing the clonogenic activity of patients' erythroid progenitors, as well as in vitro adding pegIFN and RBV to liquid cultures obtained from CD34+ cells of healthy volunteers. The majority of patients developed anaemia; the week 4 mean haemoglobin decrease was greater in HCV than in HBV patients (1.7 vs 0.47 g/dL, P = 0.01). Only three HCV patients (17%) and no HBV patients showed signs of haemolysis. The 15 nonhaemolytic HCV patients and all HBV patients showed a delay in erythroid differentiation, with a reduction in colony number and a relative increase in undifferentiated colony percentage. Haemolytic HCV patients had an increase in colony number at week 4 of therapy. In vitro, erythroid cell proliferation and differentiation were inhibited by both pegIFN and RBV. Both pegIFN and RBV have an inhibitory effect on erythroid proliferation and differentiation.     

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