J. García-Samaniego

Historical epidemiology of hepatitis C virus (HCV) in selected countries

Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6 358 000 cases in 2008 and Brazil with 2 106 000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV‐infected populations are critical for addressing HCV‐related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.

Strategies to manage hepatitis C virus (HCV) disease burden

The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV‐related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3–5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical.

Liver cirrhosis in HIV-infected patients: prevalence, aetiology and clinical outcome

Summary.  Liver disease is frequently seen in HIV+ patients as a result of coinfection with hepatitis B (HBV) or C (HCV) viruses, alcohol abuse and/or exposure to hepatotoxic drugs. The aim of this study was to assess the prevalence of liver cirrhosis, its main causes and clinical presentation in HIV+ patients. Observational, cross‐sectional, retrospective study of all HIV+ individuals followed at one reference HIV outpatient clinic in Madrid. Liver fibrosis was measured in all cases using transient elastometry (FibroScan®). All 2168 HIV+ patients on regular follow‐up (76% males, 46% injecting drug users) were successfully examined by FibroScan® between October 2004 and August 2006. Liver cirrhosis was recognized in 181 (overall prevalence, 8.3%), and the main aetiologies were HCV, 82.3%; HBV, 1.6%; dual HBV/HCV, 2.8%; and triple HBV/HCV/ hepatitis delta virus (HDV) infection, 6.6%. The prevalence of cirrhosis differed among patients with distinct chronic viral hepatitis: HCV, 19.2%; HBV, 6.1%; HBV/HCV, 41.7%; and HBV/HCV/HDV, 66.7%. In 12 patients with cirrhosis (6.7%), no definite aetiology was recognized. Overall, cirrhotics had lower mean CD4 counts than noncirrhotics (408 vs 528 cells/μL respectively; P = 0.02), despite similar proportion of subjects with undetectable viraemia on highly active antiretroviral therapy. Clinical manifestations of liver cirrhosis were: splenomegaly, 61.5%; oesophageal varices, 59.8%; ascites, 22.6%; encephalopathy, 12.1%; and variceal bleeding, 6.1%. Liver cirrhosis and hepatic decompensation events are relatively frequent in HIV+ individuals. Chronic HCV and alcohol abuse, but not chronic HBV, play a major role. Transient elastometry may allow the identification of a significant number of HIV+ individuals with asymptomatic liver cirrhosis.

Consensus conference on chronic viral hepatitis and HIV infection: updated Spanish recommendations

Summary.  Chronic hepatitis B and C represent a leading cause of morbidity and mortality among human immunodeficiency virus (HIV)‐infected patients worldwide. New treatment options against both hepatitis B (HBV) and C (HCV) viruses have prompted us to update previous recommendations for the management of coinfected individuals. Fifteen topics (nine related to HCV, five to HBV and one to both viruses) were selected for this purpose. A panel of Spanish experts in the field was invited to review these areas and propose specific recommendations, which were scored according to the Infectious Disease Society of America (IDSA) grading system. These guidelines represent a comprehensive and updated overview on the management of hepatitis B and C in HIV‐infected patients.

Lack of hepatitis E virus infection in HIV patients with advanced immunodeficiency or idiopathic liver enzyme elevations.

Summary.  Hepatitis E virus (HEV) is an enterically transmissible RNA agent that causes self‐limited acute hepatitis. Recent reports have highlighted that organ‐transplant recipients may develop chronic hepatitis E and progress to cirrhosis. Similar cases could occur in HIV patients. We have investigated 50 HIV‐infected individuals with CD4 counts <200 cells/mm3 and 43 with cryptogenic hepatitis. None of them showed HEV viremia. Thus, HEV infection does not seem to be prevalent in the HIV population and accordingly universal HEV vaccination is not warranted in these patients.

Level, phenotype and activation status of CD4+FoxP3+ regulatory T cells in patients chronically infected with human immunodeficiency virus and/or hepatitis C virus

CD4+ regulatory T (Treg) cells have been involved in impaired immunity and persistence of viral infections. Herein, we report the level, phenotype and activation status of Treg cells in patients chronically infected with human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV). Expression of CD25, CD45RA, CD27, CD127 and CD38 was assessed on these cells using polychromatic flow cytometry in 20 healthy controls, 20 HIV‐monoinfected, 20 HCV‐monoinfected and 31 HIV/HCV‐co‐infected patients. Treg cells were defined as CD4+forkhead box P3 (FoxP3)+. The percentage of Treg cells was increased significantly in HIV patients compared with controls. Moreover, there was a significant inverse correlation between CD4 counts and Treg cell levels. Fewer than 50% of Treg cells expressed CD25, with differences in terms of CD127 expression between CD25+ and CD25(–) Treg cells. CD4+Foxp3+ Treg cells displayed predominantly a central memory phenotype (CD45RA–CD27+), without differences between patients and healthy controls. Activated Treg cells were increased in HIV patients, particularly considering the central memory subset. In summary, HIV infection, but not HCV, induces an up‐regulation of highly activated Treg cells, which increases in parallel with CD4 depletion. Hypothetically, this might contribute to the accelerated course of HCV‐related liver disease in HIV‐immunosuppressed patients.

Critical role of ribavirin for the achievement of early virological response to HCV therapy in HCV/HIV-coinfected patients

Summary.  The response to hepatitis C virus (HCV) therapy seems to be lower in HCV/HIV‐coinfected patients than in HCV‐monoinfected individuals. Given that most pivotal trials conducted in coinfected patients have used the combination of pegylated interferon (pegIFN) along with fixed low doses (800 mg/day) of ribavirin (RBV), it is unclear whether HIV itself and/or suboptimal RBV exposure could explain this poorer outcome. Two well‐defined end points of early virological response were evaluated in Peginterferon Ribavirina España Coinfección (PRESCO), a multicentre trial in which the combination of pegIFN plus RBV (1000 mg if body weight <75 kg and 1200 mg if >75 kg) was prescribed to coinfected patients. For comparisons, we used unpublished data from early kinetics in two other large trials, one performed in HIV‐negative patients [Pegasys International Study Group (PISG)] in which RBV 1000–1200 mg/day was used and another [AIDS Pegasys Ribavirin Coinfection Trial (APRICOT)] in which HIV‐positive patients received fixed low RBV doses (800 mg/day). A total of 348 HCV/HIV‐coinfected patients from the PRESCO trial were analysed as well as all patients treated with pegIFN plus RBV, who completed 12 weeks of therapy in the comparative studies (435 in PISG and 268 in APRICOT). Negative serum HCV‐RNA at week 4 (which has the highest positive predictive value of sustained virological response, SVR) was attained in 33.3%, 31.2% and 13% of treated patients with HCV genotype 1, respectively, in PRESCO, PISG and APRICOT. For HCV genotypes 2/3, responses were 83.7%, 84.2% and 37%, respectively. A decline lower than 2 log10 at week 12 (which has the highest negative predictive value of SVR) was seen in 25.5%, 19.5% and 37% of HCV genotype‐1‐infected patients, and in 2.1%, 2.9% and 12% of genotypes‐2/3‐infected patients, respectively. Prescription of high RBV doses enhances the early virological response to HCV therapy in HCV/HIV‐coinfected patients, with results approaching those seen in HCV‐monoinfected patients.

Retreatment for 24 vs 48 weeks with interferon-alpha2b plus ribavirin of chronic hepatitis C patients who relapsed or did not respond to interferon alone.

We assessed the efficacy of interferon (IFN) plus ribavirin over 24 or 48 weeks for the retreatment of patients with chronic hepatitis C who had relapsed or did not respond to a previous course of IFN. One‐hundred and twenty patients (69 non‐responders and 51 relapsers) were randomly assigned to receive IFN‐α2b (3 million units thrice weekly) plus ribavirin (1000–1200 mg per day) for 24 weeks (group A: 58 patients) or 48 weeks (group B: 62 patients). Treatment was discontinued at week 12 if the alanine aminotransferase (ALT) level remained elevated. The rate of sustained response was 15.5% in group A and 37.1% in group B (P=0.013). Relapsers treated for 48 weeks had a sustained response rate of 66.6% compared with a sustained response rate of only 25% in those treated for 24 weeks (P=0.004). Moreover, a sustained response was seen in 14.3% of non‐responders treated for 48 weeks and in 8.8% of those treated for 24 weeks (P=0.71). Fifty‐three per cent of patients with a normal ALT level and undetectable hepatitis C virus (HCV) RNA at week 12 had a sustained response compared with 14% of those who were HCV RNA positive at week 12 (P < 0.001). Independent predictive factors of sustained response were: therapy for 48 weeks (P=0.0026), relapse after IFN treatment (P=0.0006), loss of HCV RNA at week 12 (P=0.0008) and HCV genotype non‐1 (P=0.024). Hence, in patients with chronic hepatitis C who failed to respond to a previous course of IFN monotherapy, combination therapy with IFN plus ribavirin for 48 weeks seems to be more effective than IFN plus ribavirin for 24 weeks.

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.

Incidence of anaemia and impact on sustained virological response in HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin.

Summary.  Ribavirin (RBV) exposure is important for maximizing the response to chronic hepatitis C virus (HCV) therapy. However, RBV‐associated haemolytic anaemia may force dose reductions or even treatment discontinuation. The use of zidovudine might further increases the risk of anaemia in HCV/HIV‐coinfected patients. The predictors of anaemia were examined in PRESCO, a large trial conducted in HIV/HCV‐coinfected patients treated with pegylated interferon alpha‐2a 180 μg/week plus RBV 1000–1200 mg/day. Measurements included maximal decrease in haemoglobin (Hb) throughout treatment, drops in Hb to <10 (moderate) or to <8.5 g/dL (severe), and premature RBV discontinuation because of anaemia. Finally, the impact of anaemia on sustained virological response (SVR) was assessed. Moderate or severe anaemia occurred, respectively, in 51 (13%) and 13 (3.3%) of 389 patients included in the study. Lower baseline Hb [RR: 0.14 (95% CI 0.07–0.27); P < 0.0001] and greater Hb drops during the first 4 weeks of therapy [RR: 4.74 (95% CI 2.95–7.60); P < 0.0001] were independent predictors of moderate anaemia at any time point in the multivariate analysis. Mean drops in Hb from baseline to week 4 were significantly greater in patients receiving zidovudine compared with other drugs (−3.09 vs−2.3 g/dL; P < 0.001). Lower baseline Hb [RR: 0.33 (95% CI 0.11–0.95); P = 0.04] and maximal Hb drops during treatment [RR: 2.48 (95% CI 1.33–4.59); P = 0.004] predicted treatment discontinuation because of anaemia. However, maximal Hb drops, development of moderate–severe anaemia and RBV dose reductions were comparable among patients who achieved SVR and those who did not. Lower baseline Hb predicts maximal drops in Hb and development of anaemia in HIV/HCV‐coinfected patients treated with pegylated interferon plus RBV. The use of zidovudine is associated with greater Hb declines at week 4. However, severe anaemia is relatively infrequent and seems not to have much impact on SVR. Given the availability of alternative antiretroviral drugs, it is advised to avoid zidovudine while receiving anti‐HCV treatment.