Treatment of Hepatitis C in children

Paloma Jara; Loreto Hierro
Posted: 03/02/2010;
Expert Rev Gastroenterol Hepatol. 2010;4(1):51-61.
© 2010 Expert Reviews Ltd.

Abstract and Introduction

Abstract

Hepatitis C affects 4–10% of children born to infected mothers, and 80% of them develop chronic infection. Most patients with chronic hepatitis C virus infection are asymptomatic, with persistent or intermittent biochemical abnormalities. Severe liver disease may develop 10 years after onset of infection, with a less than 2% overall risk during the pediatric age. Available therapies have no contraindication in children if otherwise healthy. The US FDA and EMEA have recently approved combined pegylated-IFN-α2b plus ribavirin treatment for children, who should be over 3 years of age in order to avoid severe side effects. Experiences in pilot trials and international studies indicate a response rate of 50% in genotype 1 patients, and more than 90% in genotype 2 or 3 patients, indicating resolution of chronic disease.

Introduction

The possibility of curing chronic hepatitis C virus (HCV) infection by means of PEG-IFN plus ribavirin – the currently recommended treatment – has raised controversy about the convenience of treating pediatric patients. As children with chronic HCV infection are usually asymptomatic and rarely develop severe liver damage, the possibility of eliciting adverse effects from current therapies must be appropriately balanced against the benefits. Characteristics of HCV infection in children and the results of treatment are reviewed here in order to substantiate decisions.

The discovery of HCV and the use of anti-HCV levels as a marker of exposure was available in the early 1990s to exclude infected blood and organ donors. Before this, most HCV infections were acquired by transfusions or inadequately sterilized needles or instruments. Pediatric populations heavily affected in the past due to repeated administration of blood derivatives for hemoglobinopathies, hemophilia or cancer treatment are now young adults, and therefore beyond the scope of this revision. In certain areas of the world, post-transfusional hepatitis C remains a hazard. Cumulative information on superimposed HCV infection to some underlying diseases of children indicates similar chronicization rates, deleterious effects of iron overload added to viral-induced liver damage and evidence of difficult-to-treat patients because of conditions that affect the tolerability of drugs, such as anemia or renal insufficiency.

The effectiveness of excluding parenteral routes of HCV is demonstrated in young populations of industrialized countries.[1] Perinatal mother-to-child transmission accounts for 95% of all cases of hepatitis C in children born after 1990. In addition, over the years there has been a reduction in the number of pediatric cases of vertical transmission because the anti-HCV-positive rate has decreased in younger women as a result of lesser transfusional transmission of the disease, and due to changes in illicit drug abuse with a shift towards nonintravenous forms of administration.[2]

In the current setting, most affected children are otherwise healthy. The applicability of treatment is the rule. Combined treatment offers a 50–90% chance (according to HCV genotype) of clearing HCV infection, thus avoiding the progression of liver disease. This review will focus on the benefits of current therapy, mostly evident in the long term, and also on drug toxicity.

Origin of HCV Infection in Children: Mother-to-child Transmission

Hepatitis C is an asymptomatic disease in infants. The only efficient method for its detection is the investigation of children at risk. Infants of women with hepatitis C should be tested for HCV RNA on two occasions, between the ages of 2 and 6 months, and again at 18 to 24 months, along with serum anti-HCV.[3–5] Variants to this schedule are also employed. Tests performed in umbilical cord or before 1 month of age give a high rate of false-negative and false-positive results and are not recommended.

The offspring of anti-HCV-positive mothers have anti-HCV antibodies in their blood as a result of passive transplacental transfer. These antibodies remain detectable in the infant for the first 12–15 months of life. The definition of mother-to-child transmission of HCV includes: the detection of anti-HCV antibodies in a child over 18 months of age, or the detection of HCV RNA in a child over 2 months of age, preferably confirmed in two different samples.[3]

Children born to anti-HCV-positive and HCV RNA-positive mothers have an infection risk of 4–10%, with no differences between caesarean or vaginal delivery, or between children who are breastfed or receive infant formulas.[3,6] Once pre- or peri-natal transmission has been discarded, cohabitation of the child with the mother entails no appreciable risk.

Excellent reviews on HCV vertical transmission are available.[3,6,7] Some risk factors have been clearly identified, such as maternal viremia[4,8] or maternal co-infection with HIV-1.[3] Maternal intravenous drug use, the presence of HCV RNA in maternal peripheral blood mononuclear cells and genetic factors (HLA-DRB1*10 in children) could also facilitate transmission.[9–11]

However, discordance exists between studies. Viral load in the mother is a rational risk factor involved in transmission to the child, but was found to be either high or not significantly different between transmitting and nontransmitting mothers.[8,12] Other risk factors are linked to abnormal labor, as published data support facilitated transmission by a prolonged time from rupture of membranes to birth.[6,13,14] Antiretroviral treatment of HIV-infected mothers decreases the risk of HCV transmission to levels similar to HIV-negative mothers.[6]

Mother-to-child transmission theoretically can occur in utero, at the end of pregnancy or at delivery. Among 54 infected infants tested within 3 days of birth, 31% displayed HCV viremia, suggesting that intrauterine infection could have occurred.[15]

There are currently no established interventions to prevent infection of the child born to an infected mother. In particular, there is no evidence to suggest that women should be offered an elective caesarean delivery or be advised to avoid breastfeeding.[4]

Course of HCV Infection in Children

In order to know the characteristics of HCV infection in children from the onset, many studies aimed at the surveillance of children born to HCV-positive mothers. HCV screening is not mandatory in pregnant women, as no intervention can be carried out to prevent transmission. In large hospital series, the rate of anti-HCV-positive women is approximately 0.6%, of whom 60% are viremic. The reduced number of infected children (4–10% of those born from viremic mothers) requires collaborative studies, with an extended time for recruitment of children from several centers.

No symptoms are observed at the beginning of hepatitis C. In a series of 70 children with vertical transmission, the majority (93%) developed aminotransferase elevations 1.2- to 21-times the normal values in the first year of life, with maximum values occurring either in the first or second semester.[16] None developed hepatitis with jaundice. Overall, 62 out of 70 children could be followed up to 24 months of age or more. The cumulative probability of HCV RNA persistence was 90% at 2 years, 81% by the end of the third year of life and 81% at the fifth year. A sustained alanine aminotransferase (ALT) normalization with clearance of HCV RNA was observed in 12 out of 62 (19%) patients starting from the second year of life or the beginning of the third year. All those cured children remained anti-HCV positive.[16]

According to the European Pediatric Hepatitis Network (EPHN) the estimated proportion of children with clearance of viremia, out of 155 children with HCV infection observed from birth, was 17% by 2 years of age, 24% by 3 years and 30% by 5 years.[17] No patient cleared infection beyond the fifth year. The tendency towards chronicity showed no gender-based difference. In contrast to the aforementioned study, many of the children with a resolved infection evolved to a negative anti-HCV status in this study.

A retrospective Canadian study on 39 children with neonatal infection found a 25% probability of clearing infection by 7 years of age. Clearance occurred in 30% of nontransfusional and 16% transfusion-associated hepatitis C. No further clearance was observed beyond 7 years.[18]

Genotype influences clearance rates. Children with genotype 3 infection had the highest ALT levels and the highest rate of spontaneous viremia clearance.[16] In a series of 119 Italian cases diagnosed within the first 3 years of life, clearance rates were 5, 2.5, 7, 32 and 6% for genotypes 1a, 1b, 2, 3 and 4, respectively.[19]

Overall, prospective studies show that 80% of children develop chronic infection, the diagnosis being established in those who remain HCV RNA-positive at 3 years of age. Spontaneous clearance after that time is unlikely.

The chronicity rate of HCV in children infected at birth does not differ from that of adults or children infected at older ages. Nearly 70% of children with inherited bleeding disorders or leukemia develop chronic infections.[20,21] Serologic cross-sectional surveys show that 75–85% of anti-HCV-positive adults display positive HCV RNA. However, some series of children infected during cardiac surgery and two cohorts of young women infected by contaminated immune globulin had a chronic infection rate of 55%.[22–24]

Liver Damage in Pediatric Chronic HCV Infection

Data are derived from vertically infected children identified in prospective studies and series of children who were found to have HCV chronic infection at varying times of life, when screened because of risk exposures or asymptomatic aminotransferase elevation. Provided the children are otherwise healthy and not affected by chronic illnesses, the characteristics of chronic HCV infection are not related to the mode of infection acquisition (parenteral or vertical route).[25]

Chronic HCV infection is usually an asymptomatic disease. Nearly 15% of children present nonspecific, mild and transient symptoms at the time of initial diagnosis, probably related to intercurrent illness that leads to HCV detection. Hepatomegaly is noted in 10% of infants. HCV-associated cryoglobulinemia, vasculitis and porphyria cutanea tarda are not reported.

During chronic infection, different patterns of biochemical abnormalities are observed. In two large series of 194 and 332 children, respectively, ALT levels were persistently abnormal in 42–45% of patients, normal or normalized in 8–23% and intermittently elevated in 35–41%.[26,27]

The predominant genotypes in European and American children are 1a and 1b (70%), although in recent years, and considering children with vertical transmission, the proportion of genotype 1 infections has decreased to 54%, with a rise in genotypes 3 (23%) and 4 (7%).[19] The viral load does not appear to be correlated to ALT levels or the histologic lesions.[28]

A biopsy is needed for accurate assessment of lesions produced by chronic hepatitis. Although not performed in every affected child, it usually reveals mild lesions. Noninvasive biochemical tests (Fibro-Test and Acti-Test) are being evaluated in children with hepatitis C for their correlation with histology.

In a study of Italian and Spanish children, the histologic activity index (HAI) was found to be low in most patients, with a mean value of 3.6 (range 0–11). The final diagnoses were normal liver histology or with minimal and nonspecific lesions in 17.5% of the cases, chronic hepatitis with a low activity in 60% and high activity in 21%. Those patients with a definitive diagnosis of highly active chronic hepatitis were significantly older on average (12 years) than children with low-activity chronic hepatitis or minimal liver lesions (8 years). Fibrosis was absent in 27.5% of cases, mild in 55% and moderate in 16.2%. Only 1.3% (one of the 80 children) had cirrhosis. A significant relationship was detected between fibrosis scores and duration of disease, portal inflammation and interface hepatitis.[29]

In a later report with additional children (total of 112 cases) fibrosis was assessed by the METAVIR scale.[30] Age of patients at biopsy and duration of infection strongly correlated with fibrosis stage. A strong difference was observed between patients whose infection lasted less and more than 10 years. The mean rate of 'estimated' fibrosis progression in a linear progression model was 0.227 ± 0.372 METAVIR units per year, with a median of 0.142. Theoretically, cirrhosis could develop after a mean time of 28 years. However, the rate of 'observed' fibrosis progression per year in the 13 subjects who underwent paired biopsies was variable among them (seven had increased and six unchanged scores), averaging 0.112 ± 0.14. The progression of fibrosis seems to be a function of the duration of the infection, when no other risk factors for liver damage are present.

Similar histologic findings have been reported in several series, some of which included patients affected by other superimposed conditions to HCV (Table 1).[26,31–34]

A recent report on 121 children without decompensated disease and recruited in several American centers for a therapeutic trial[34] has shown that children with normal ALT were as likely to have significant inflammation as those with elevated ALT levels. Five patients (4.2%) had bridging fibrosis and two (1.7%) had cirrhosis. There was a highly significant correlation of inflammation with fibrosis. In the subset of 94 children with perinatal transmission, there was a weak correlation of estimated duration of disease with inflammation that approached statistical significance. The two children with cirrhosis were both 14 years old, whereas the five with bridging fibrosis were 11–16 years old. The lack of correlation of age or duration of infection with fibrosis might have been due to the small number of patients with advanced fibrosis.

Other authors found the severity of liver disease did not seem to depend on the duration of infection.[31

Severe Liver Disease in Children

In a series of 332 persistently viremic Italian children, who were otherwise healthy, six patients (1.8%) with high ALT levels developed signs and symptoms of advanced liver disease (asthenia, epistaxis, pruritus, ascites and gastrointestinal bleeding). Two patients developed decompensated liver disease at a very young age (2 and 5 years, respectively); however, most cases of advanced disease were older (age 11–15 years).[27] Genotype 1a was involved in five cases. None of these children had a history of drug or alcohol abuse, nor were they obese.

Decompensated liver disease was observed in one out of 194 (0.5%) children included in a multicenter European study.[26] This patient had a history of blood transfusions for hemolytic–uremic syndrome at the age of 3 years. Liver transplantation was needed when he was 19 years of age. The infection was due to HCV genotype 1a, and liver–kidney microsomal antibody type 1 (LKM1) was found to be positive.[35]

LKM1 antibodies are detected in 6–10% of children with chronic HCV infection. Overall, features of these patients help to differentiate them from those with autoimmune hepatitis. Coexistence of LKM markers was associated with a higher than expected rate of significant fibrosis (Ishak score >3 in 27%) in a series comprising 21 patients.[35]

Other cases of severe liver disease in childhood have been reported occasionally. A quaternary referral center in the USA described seven cases (7.7% of 91 referred patients) aged 4–18 years old (mean 11 years).[36] Other authors reported two 14-year-old adolescents, one of them without comorbid conditions, with cirrhosis and hepatocellular carcinoma.[37]

The small proportion of children with chronic hepatitis C leading to liver failure is confirmed in liver transplantation registries, as HCV comprises less than 1% of the indications in children.[38] Among 63 cumulative pediatric cases (1988–2005) undergoing transplantation for HCV end-stage disease in the USA, 88% were over 10 years old.[39]

Outcomes in Adult Age

An assessment of the characteristics of liver disease in adults who acquired HCV infection in childhood is available for certain populations of patients. Overall, patients who acquired HCV by parenteral routes predominate, and many were affected by transient or persistent conditions that may influence outcome. A report on 11 patients infected at birth by the same blood donor found, by the age of 35 years, nine cases with no fibrosis or mild fibrosis and one each with discrete (Ishak 3) or marked (Ishak 4) fibrosis.[40] Similar findings were obtained in children who acquired HCV infection after cardiac surgery, and in a series of leukemia survivors.[21]

Since there are no prospective studies on the course of the infection from infancy to adulthood, the data provided by studies in adult patients are of interest. In these studies, infections beginning before 40 years of age presented a severe liver disease rate of only 2–8% after 20 years, while infections developing after age 40 years yielded a 20% cirrhosis rate after 20 years. The estimation of the percentage of patients that develop severe disease in the course of a lifetime varies according to the different studies. In the period of 20 years after first infection, 20% of the patients seen in referral centers developed cirrhosis, although in the case of patients identified through screening of the general population or blood donors, only 4–7% were found to have cirrhosis.[41]

Treatment

There are different approaches to the treatment of children with chronic hepatitis C.[42] The main characteristic of chronic hepatitis C is its persistence over time with slow progression to fibrosis. Severe disease is rare in children, and therefore follow-up without treatment until adult life is a valid option for most pediatric patients. Treatment during childhood does not achieve increased rates of response compared with adult patients and adverse effects are frequent and, even in some cases, may be severe. Conversely, treatment may be justified, since it allows definitive resolution in a subgroup of patients. Quality of life is not affected in children with HCV infection, but parents are worried about the outcome and perceive the difficulties of social life, even when there is a negligible risk of horizontal transmission.[43,44] Adolescence and young adulthood are associated with high scholar or work demands, and more difficult compliance with medical visits. All those factors may lead to postponed treatment.

The decision to treat should consider several aspects in the individual patient: age, severity of disease, efficacy of the chosen therapy, its adverse effects, compliance to treatment and willingness. Children under 3 years old are not eligible for treatment (and treatment is not approved), as HCV infection may still spontaneously resolve and spastic diplegia has been reported in infants treated with IFN-α for hemangiomas.[45]

Over time, and in parallel with the results obtained in adults, experience has been gained in children with IFN-α monotherapy,[46–50] the combined use of IFN-α and ribavirin,[51,52] pegylated IFN (PEG-IFN) monotherapy[53] and, at present, the use of PEG-IFN with ribavirin, which was approved by the US FDA (in December 2008) and the EMEA (in December 2009) for children older than 3 years of age.

Baseline Patient Evaluation

Patients are excluded if they have comorbid medical conditions (i.e., moderate or severe depression, psychiatric conditions, seizures and renal insufficiency) that could compromise the tolerability of the drugs. Patients testing positive for autoimmunity markers – antinuclear antibody, smooth muscle antibody and LKM1 – are enrolled if other features do not suggest autoimmune hepatitis. Adolescents should be instructed in birth control during antiviral therapy and for 6 months after treatment cessation. Routine pregnancy testing is advised in girls of child-bearing potential.

The viral genotype involved must be known in order to assess the probability of response and to design the duration of therapy. Viral load must be quantified since the decision to maintain therapy will depend on the course of viraemia at week 12 of treatment in the case of genotypes other than 2 and 3. A biopsy is recommended before starting treatment. According to several studies performed on pediatric chronic HCV infection histology, showing mild lesions in most, the need for a biopsy to assess the disease is controversial, although it is the only method to identify severe cases. However, treatment decisions should not rely on histological findings.

Further workout should be carried out, especially in line with recent observations of genetic polymorphisms linked to response to treatment, which can be of value for treatment decisions in the future. Candidate studies are polymorphisms near the IL28B gene, encoding IFN-λ-3, which has been associated with an approximately twofold change in response to treatment.[54]

Treatment Design

Common terminology refers to 'rapid viral response' when viremia turns undetectable in week 4 of treatment, 'early viral response' when HCV RNA is negative in week 12 and 'end of treatment response' when viremia proves negative at the end of treatment. Sustained virologic response (SVR) is defined as undetectable serum HCV RNA 24 weeks after treatment cessation and is equivalent to resolution of infection.

In treatment-naive patients, the likelihood of achieving a SVR is best predicted by a more than 2 log10 unit decrease in HCV RNA by 12 weeks of therapy. Among naive populations, less than 2% of patients who fail to achieve an early virological response ultimately achieve a SVR.

Therapy aims to achieve negative conversion of HCV viremia to below the detection limit of the qualitative PCR technique employed (30–50 IU/ml). Once negativity has been achieved, treatment must continue long enough to ensure eradication of the infection in the liver. Different HCV genotypes exhibit different sensitivities to treatment. Genotypes 2 and 3 are more sensitive, with healing rates of 83–100% of all patients treated for 24 weeks. In the case of genotypes 1 and 4, the overall SVR rate is 50%, and 48 weeks of therapy are required. The high probability of a favorable response in the case of a sensitive genotype means all patients need treatment for 24 weeks. In the case of less-sensitive genotypes, re-evaluation is carried out after 12 weeks. If at this point there has been a decrease in viral load of at least 2 log10, treatment is continued up to 48 weeks. However, if such a decrease in viral load is not found, treatment is withdrawn, since healing is not likely to occur even if the full treatment course is administered.

Guidelines of treatment are well established in adults.[55] In these patients current studies aim to shorten the duration of therapy (to 16 weeks in the case of a sensitive or favorable genotype, and to 24 weeks in the case of genotype 1) for those subjects with rapid viral response, and to prolong therapy (48 weeks for genotype 3 and 72 weeks for genotype 1) for those subjects showing a drop in viremia, but with persistent positive HCV RNA at week 12. Other ongoing investigations aim to increase efficacy by adding antiviral agents, such as telaprevir or boceprevir, to the conventional PEG-IFN plus ribavirin treatment.[56]

Drugs

Pegylated IFN-α Pegylated IFN-α is created by covalently linking a polyethylene glycol moiety to the IFN-α protein. The addition of this moiety to IFN-α confers an extended serum half-life compared with native IFN-α, allows once-weekly dosing and significantly improves SVR rates. Two forms of PEG-IFN have been developed, PEG-IFN-α-2b and PEG-IFN-α-2a. PEG-IFN-α-2a uses a large (40 kD) branched polyethylene glycol molecule, while PEG-IFN-α-2b uses a smaller (12 kD) linear molecule. The overall results from controlled trials in adults suggest that they achieve a similar rate of SVR.

Adverse events of PEG-IFN occur in the same proportion of patients and are of the same quality as observed with IFN-α. PEG-IFN is more convenient because of the weekly administration and influenza-like symptoms being limited to one versus three doses per week with conventional IFN.

Dosing in Children A once-weekly dose of PEG-IFN-α-2a is calculated from each patient's body surface area according to the formula BSA (m2)/(1.73 m2) × 180 µg. This dosing achieves adequate therapeutic concentrations.[53]

PEG-IFN-α-2a 1–1.5 µg/kg once a week has been given to children after approval in adults. Another approach is to adjust the adult dosing of 1.5 µg/kg to the body surface of the child, so dosing for children results in 60 µg/m2 per week.

The PEG-IFN-α dose is transiently decreased in patients with a neutrophil count of less than 1–1.25 × 109 cells/ml to avoid significant neutropenia. PEG-IFN-α is temporarily discontinued if the neutrophil counts fall below 0.75–1.00 × 109 cells/ml; and it is resumed once the neutrophil counts recover.

Ribavirin Ribavirin is a guanosine analog. Ribavirin alone has a relatively minor antiviral effect in HCV-infected patients, but in combination with PEG-IFN-α it appears to enhance the second and third phases of viral decay, thereby reducing the chance of relapse.[57] Its suggested mechanisms of action include error catastrophe resulting from mutagenesis via incorporation of ribavirin into HCV RNA during replication, direct inhibition of HCV RNA replication, inosine-monophospatedehydrogenase inhibition and immunomodulation. A relationship between ribavirin dose and response to therapy with both IFN-α-2a and -α-2b has been established, especially in patients with HCV genotype 1.

Ribavirin is cleared by the kidneys, so it should be reduced in patients with decreased creatinine clearance and completely avoided in renal insufficiency. Its main toxicity is hemolytic anemia, directly related to the concentration of ribavirin in erythrocytes. Anemia is the most common reason for ribavirin dose reduction or treatment discontinuation.

Dosing in Children A study in children receiving IFN-α-2b plus ribavirin 8, 12 or 15 mg/kg/day demonstrated that those on 15 mg/kg had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12, with an acceptable safety profile.[52]

On-therapy Assessments in Children

For assessment of efficacy, HCV RNA titers are measured at weeks 4, 12, 24 and 36, at the end of treatment, and every 12 weeks for another 6 months after the end of treatment. The assessment of safety should be planned in order to promptly detect adverse effects that require dose adjustment. Drugs cause influenza-like symptoms, neutropenia, anemia and weight loss especially during the first month of treatment. Clinical and analytical follow-up is performed every 2 weeks in the first phase of therapy. Monthly visits are advisable up to the sixth month, and scheduled every 3 months for the remaining period of treatment and for another 6 months after the end of treatment. Depression, thyroid disorders and growth velocity should be assessed. The long-term effects on thyroid function (if disturbed during treatment) and on growth would require an extended time (i.e., 2 years) of follow-up.

Efficacy of PEG-IFN Plus Ribavirin Treatment in Children

Combined therapy with PEG-IFN and ribavirin has improved sustained response rates compared with other treatments and currently represents the standard therapy in adult patients.

There are two ongoing trials in children with almost finished efficacy reports.[58–60] One international study investigates the pharmacokinetics, efficacy and safety of PEG-IFN-α-2b 60 µg/m2/week combined with ribavirin 15 mg/kg/day in 107 children. Another multicenter North American trial investigates PEG-IFN-α-2a plus ribavirin (55 children) compared with PEG-IFN-α-2a monotherapy (59 children) (Table 2).

Two European studies have been published with the data on the efficacy and adverse effects of the PEG-IFN plus ribavirin combination in children. One was conducted in a center in Spain; 30 children (24 naive) were enrolled to receive PEG-IFN-α-2a 1 µg/kg/week with ribavirin 15 mg/kg/day.[61] The other trial was carried out in several centers in Germany, and 61 children (51 naive) were given PEG-IFN-α-2a 1.5 µg/kg/week plus ribavirin 15 mg/kg/day.[62] In both studies the duration of treatment was 24 or 48 weeks in genotype 2/3 infections, and for 48 weeks in the case of genotype 1 or 4. The results were similar in both (Table 2), and showed a response equal to or slightly greater than that reported in children on conventional IFN-α given three-times per week plus ribavirin.

In the Spanish study, involving strict chronic infection inclusion criteria (over 3 years from infection), and with a patient age of 3.5–16 years, 69% of the cases were due to mother-to-child transmission, 86.6% corresponded to genotype 1, and baseline viral load was >5 log10 IU/ml in 66.6% of cases. SVR was achieved in 15 (50%) of 30 patients: in three (100%) out of three patients with HCV genotype 3, and in 12 (44%) out of 27 with HCV genotype 1. One patient with HCV genotype 4 did not respond. All patients who attained SVR remained HCV RNA-negative at further follow-up visits (up to 36 months) and had normal liver function.[61]

In the German study, the patients were between 2–17 years of age; 40.3% of the infections were the result of vertical transmission and 75.8% presented genotype 1. Of 46 patients with genotype 1, 22 (47.8%) showed SVR. All individuals with genotype 2 or 3 (n = 13) responded permanently, irrespective of the duration of treatment (i.e., 24 or 48 weeks) (p < 0.0003). One of two patients with genotype 4 had SVR.[62]

Predictors of Response

The study of baseline characteristics of treated patients may help to identify predictors for response, in order to select the candidates for therapy. Among adult patients, those aged less than 40 years without advanced disease show better response rates. However, overall results of treatment during childhood do not clearly offer significantly better results compared with adults.

The most important determinants of response in children are the viral genotype and viremia levels among those with genotype-1 infection. No baseline characteristic excludes response to therapy among those with genotype 1. On the other hand, the evolution of viremia after 12 weeks of therapy is of much help to identify future responders. In practical terms, all children may be eligible for treatment and early stopping rules according to week 12 viremia should be applied.

The HCV genotype is the main baseline predictor of response. Recent unpublished pediatric trials obtained a response in 93% of genotype 2 or 3, 80% of genotype 4 and 53% of genotype 1 HCV infections, and 47% of genotype 1 compared with 80% of genotype non-1, respectively.[58,60] In the international PEG-IFN-α-2a plus ribavirin study, response in genotype 1 was influenced by baseline viral load, as those showing HCV-RNA over 6 × 105IU/ml had 29% SVR compared with 72% SVR in genotype 1 with lower titers.[58]

Patient age does not seem to influence response (SVR: age < 12 years versus older children: 54.8 vs 63.3% in the German study and 45 vs 60% in the Spanish study). Responders show similar baseline ALT levels compared with nonresponders, and children with normal aminotransferase values display the same SVR rate as those with abnormal biochemistry prior to therapy. The baseline viral load and Knodell index did not influence the response in the Spanish study. However, in both experiences, the response in those children who developed the infection as a result of blood transfusions tended to be higher than in those with mother-to-child transmission (German children: 70.4 vs 48%; p = 0.087; Spanish children: 78 vs 38%; p = 0.1).[61,62]

Virological surveillance while on therapy appears to be the best predictor of response. In the Spanish study, only one patient showed negative HCV RNA at week 4. At week 12 of treatment, 51.7% showed undetectable HCV RNA, while 72% presented a greater than 2 log10 decrease compared with baseline viral load. A SVR was elicited in 87 and 71% of those presenting the above characteristics, respectively, at week 12. No cases with less than 2 log10 reduction at week 12 achieved sustained response. Continued therapy for 48 weeks in six children with positive HCV RNA at week 24 was ineffective in all cases.[61]

The German study reported that 62.3% of the treated children achieved negative HCV RNA at week 12. In turn, 91% of the patients with genotype 1 and 92.3% of those with genotypes 2/3 who showed a sustained response presented undetectable viremia at week 12 of therapy.[62]

Nonresponders to Therapy

Circumstances associated with a lack of response in children have not yet been elucidated.

Children with genotype 1 infection with mother-to-child transmission, currently representing the most numerous group, have shown SVR rates of 37.5 and 35% in the Spanish and German studies, respectively.[61,62] Thus, for many patients current therapy is inefficient.

Nonresponders can be retreated, but there is a very limited experience in children. According to studies in adults, the likelihood of response to retreatment depends on the type of response to prior therapy (relapsers achieve near 40% of SVR compared with 10% in nonresponders) and the differences in efficacy between the initial and the retreatment regimens. Very few children who failed to respond with IFN-α monotherapy were retreated with IFN-α plus ribavirin,[51] or PEG-IFN-α-2a plus ribavirin.[61,62] Using the highest efficacy PEG-IFN plus ribavirin, a sustained response was achieved in three out of 11 cases.

Adverse Effects

The adverse effects of PEG-IFN plus ribavirin are similar to those associated with conventional IFN, involving fewer injections and immediate injection reactions. Other adverse effects were of the same nature and intensity.

The toxicity of PEG-IFN plus ribavirin treatment must be carefully evaluated. It has been assessed in only two studies.[61,62]

In almost all children and adolescents, transient flu-like symptoms with variable intensity, including moderate fever, are observed during the first weeks of treatment. In most of them, the symptoms resolved or were of minor intensity during the second 6 months. Febrile convulsions are a hazard in younger children, but the problem did not occur in available series. Dose reduction by 20–30% of PEG-IFN was carried out because of considerable leukopenia in 5% of patients in the German series. Prolonged (>1 month) or permanent reductions in PEG-IFN-α-2b doses were required in 23% of Spanish children (Table 3).[61,62]

Owing to hemolysis induced by ribavirin, mean hemoglobin levels decrease within the first week of therapy, reaching a mean maximal decrease of 1.4 g/dl by week 12. Hemoglobin values are stable during the remaining period and return to normal when therapy is discontinued or completed. No reduction in ribavirin dose was required. Reticulocyte levels increased during therapy but returned to normal thereafter.

School performance is not grossly affected. Transient changes in character or mood have been recorded in 15–30% of the children, but severe psychological impairment was not observed.[61,62] Depression is a concern and should be looked for in adolescents, as suicidal ideation and even suicidal attempts have been reported during treatment with conventional IFN-α plus ribavirin.[52]

Patients with detectable LKM1 antibodies at baseline have shown either stable or varying titers during therapy. No patient developed LKM1 antibodies, although previous experiences have shown that LKM1 appear in 5% of children treated with IFN-α.[35] No specific liver function events occurred in antinuclear antibody-positive or LKM1 antibody-positive patients during or after therapy. Regarding the possibility of IFN facilitating autoimmune disease, one girl was reported to have developed diabetes mellitus after 9 months of treatment; therapy was continued without changing dosage and the patient showed SVR.[62]

The emergence of thyroid antibodies and thyroid-stimulating hormone elevation during treatment is significant. In the German study, five individuals received a weight-adjusted dose of l-thyroxine until the end of treatment. In three of these, l-thyroxine could be stopped during follow-up, and in two patients thyroid hormone supplementation was maintained 12 months after discontinuation of ribavirin and PEG-IFN.[62]

According to the Spanish study, four patients developed antithyroid antibodies. Two patients showed sudden decreases in thyroid-stimulating hormone values during therapy, accompanied by high T4 values and weight loss. Treatment was discontinued immediately in both patients. Anti-thyroid antibodies appeared in successive checkups. No specific therapy for hyperthyroidism was required and thyroid-stimulating hormone and T4 values returned to normal. The remaining two patients developed antithyroid antibodies during therapy and the condition persisted when off therapy. Mild elevation of thyroid-stimulating hormone or T4 values was observed in another additional six patients.[61]

Growth during the 48-week treatment period has been shown to be reduced in most patients by a mean of 1.6 cm compared with the average growth for age and gender. Growth velocity was normal in the 6-month period after the end of treatment; however, the modest decrease in height percentile observed during therapy was not recovered in the short term.[61]

Conclusion

In conclusion, the efficacy of combined therapy in children warrants its application. A response rate of 50% in genotype 1 patients and more than 90% in genotype 2 or 3 patients is achieved, which means cure of a chronic disease. However, more in-depth studies are needed, with further investigation of the factors implicated in the development of thyroid alterations in some children.

Expert Commentary

Current treatment (PEG-IFN-α plus ribavirin) in children with chronic hepatitis C should be managed by pediatric specialists. Many individual and family variables determine the appropriate time to initiate treatment. Mid-childhood age before adolescence is preferable. Side effects are usually well tolerated, but severe adverse events may occur in a low number of children. The near complete efficacy in favorable genotypes, and the early stopping rules for genotype 1 cases shifts the balance toward applying treatment to children, although new drug investigation is needed. The mild disease that children usually present makes safer the initiation of studies once efficacy and toxicity profiles of new drugs have been assessed in adult patients.

 Five-year View

New lines of research in children are necessary to assess long-term clinical outcomes, to develop noninvasive methods for detecting fibrosis, to establish gene polymorphisms related to disease progression and response to therapy and to identify individuals at risk for significant side effects before treatment initiation. Trials with combined therapy plus antivirals should begin as soon as safety profiles have been established in adult patients.

References

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•• Description of histology in pediatric chronic hepatitis C children unaffected by any other disease.

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•• Assessment of factors involved in fibrosis progression in children.

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36.Rumbo C, Fawaz LR, Emre SH et al. Hepatitis C in children: a quaternary referral center perspective. J. Pediatr. Gastroenterol. Nutr. 43, 209–216 (2006).

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40.Casiraghi MA, de Paschale M, Romano L et al. Long-term outcome (35 years) of hepatitis C after acquisition of infection through mini-transfusions of blood given at birth. Hepatology 39, 90–96 (2004).

41.Seeff LB. Natural history of chronic hepatitis C. Hepatology 36, S35–S46 (2002).

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44.Rodrique JR, Balistreri W, Haber B et al. Impact of hepatitis C virus infection on children and their caregivers: quality of life, cognitive, and emotional outcomes. J. Pediatr. Gastroenterol. Nutr. 48, 341–347 (2009).

45.Barlow CF, Priebe CJ, Mulliken JB et al. Spastic diplegia as a complication of interferon α-2a treatment of hemangiomas of infancy. J. Pediatr. 132, 527–530 (1998).

46.Jacobson KR, Murray K. Zellos A, Schwarz KB. An analysis of published trials of Interferon monotherapy in children with chronic hepatitis C. J. Pediatr. Gastroenterol. Nutr. 34, 52–58 (2002).

47.Jara P, Hierro L, Frauca E et al. Interferon a2b treatment in children with chronic HCV hepatitis. J. Pediatr. Gastroenterol. Nutr. 24, 487 (1997).

48.Bortolotti F, Giacchino R, Vajro P et al. Recombinant interferon-α therapy in children with chronic hepatitis C. Hepatology 22, 1623–1627 (1995).

49.Iorio R, Pensati P, Porzio S, Fariello I, Guida S, Vegnente A. Lymphoblastoid interferon a treatment in chronic hepatitis C. Arch. Dis. Child. 74, 152–156 (1996).

50.Bortolotti F, Iorio R, Nebbia G et al. Interferon treatment in children with chronic hepatitis C: long-lasting remission in responders, and risk for disease progression in non-responders. Digest. Liver Dis. 37, 336–341 (2005).

51.Wirth S, Lang T, Gehring S, Gerner P. Recombinant α-interferon plus ribavirin therapy in children and adolescents with chronic hepatitis C. Hepatology 36, 1280–1284 (2002).

52.Gonzalez-Peralta RP, Kelly DA, Haber B et al. Interferon α-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology 42, 1010–1018 (2005).
•• Study on efficacy and toxicity of combined IFN-α plus ribavirin treatment in a large population of children.

53.Schwarz KB, Mohan P, Narkewicz M et al. The safety, efficacy, and pharmacokinetics of peginterferon α-2a (40 kD) in children with chronic hepatitis C. J. Pediatr. Gastroenterol. Nutr. 43, 499–505 (2006).

54.Ge D, Fellay J, Thompson AJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461, 399–401 (2009).

55.Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 49, 1335–1374 (2009).

56.Thompson A, Patel K, Tillman H, McHutchison JG. Directly acting antivirals for the treatment of patients with hepatitis C infection: a clinical development update addressing key future challenges. J. Hepatol. 50, 184–194 (2009).

57.Reddy KR, Nelson DR, Zeuzem S. Ribavirin: current role in the optimal clinical management of chronic hepatitis C. J. Hepatol. 50, 402–411 (2009).

58.Wirth S, Ribes-Koninckx C, Bortolotti F et al. Children with HCV infection show high sustained virologic response rates on peginterferon α-2b plus ribavirin treatment. Hepatology 48, 392A (2008).

59.Murray KF, Rodrigue JR, Gonzalez-Peralta RP et al. Design of the PEDS-C trial: pegylated interferon ± ribavirin for children with chronic hepatitis C viral infection. Clin. Trials 4, 661–673 (2007).

60.Schwarz KB, Gonzalez-Peralta, RP, Murray, KF et al. Peginterferon with or without ribavirin for chronic hepatitis C in children and adolescents: final results of the PEDS-C trial. Hepatology48(Suppl. 1),418A (2008).

61.Jara P, Hierro L, de la Vega A et al. Efficacy and safety of PEG-IFNα-2b and ribavirin combination therapy in children with chronic hepatitis C. Pediatr. Infect. Dis. J. 27, 142–148 (2008).
•• Experience of currently recommended therapy in Spanish children.

62.Wirth S, Pieper-Boustani H, Lang T et al. PEG-IFNα plus ribavirin treatment in children and adolescents with chronic hepatitis C. Hepatology 41, 1013–1018 (2005).
•• Experience of currently recommended therapy in German children.

Papers of special note have been highlighted as:
•• of considerable interest

Source

5-year-old's got a whole world in his hands

Elijah Richards, who's being treated for hepatitis C, holds the globe sent to him by supporters from all over the world whom his family came to know through the Internet

Published: 12:00 AM, Sun Dec 19, 2010

Kim Hasty

LAURINBURG - The Richards family is ready for Christmas. The tree and nearly every square foot of visible living space are decorated with some sort of Christmas cheer.

Cheer, in fact, is the general order of the day in this house located a bit off the beaten path of the town's main thoroughfare. The only thing more prevalent than Christmas decorations is the laughter. And in the middle of it all earlier this week was the pint-size source of much of the prevailing sense of happiness.

Sitting cross-legged, with encouragement from not one, but four, older brothers, 5-year-old Elijah was given permission to carefully unwrap the first Christmas present of the season. A little early to start opening presents, perhaps, but this one held an undeniably special significance.

The gift had come from friends. Friends from all over the world. Australia and New Zealand. Italy, France and England. From various parts of the United States, too.

Elijah opened the cushioned box. Inside, of all things, was a globe. A globe small enough that a 5-year-old could lift it out of its box and hold it carefully in his small hands. And one day come to understand its implications.

"It's wonderful they did this for him,'' said his mother, Lana.

The globe, which spins on solar power, sits on a crystal-like pedestal inscribed with these words: "Elijah Richards. Hep C Hero. Christmas 2010.''

Hero is a heavy mantle to hang on a 5-year-old, but this 5-year-old wears it well. A wiggle worm sometimes. A hero all the time.

"They call hepatitis C a dragon,'' Lana Richards said. "But Elijah's gonna beat it because he's a dragon slayer.''

Lana and Shawn Richards knew there was a chance Elijah would be born with hepatitis C because his birth mother had the disease. Hepatitis C is caused by a blood-borne virus that slowly attacks the liver over time. There is no vaccine to prevent the disease and no certain cure. Once a child is infected, the disease has historically lasted a lifetime. In the United States, about 240,000 children have been exposed to the virus.

Undaunted, the Richardses, already the parents of five children, went through with the adoption and accepted Elijah's diagnosis when it came, without flinching.

What they couldn't accept was the fact that the conventional medical practice has historically been to not treat children for hepatitis C until they begin showing symptoms of the disease, which often doesn't happen until they are adults in the prime of life. Part of the reason is that few drugs have been available for treatment in children.

Lana Richards got busy educating herself. She found two websites in particular that offered her the most comfort and the most information - hepcnomads.co.uk and hepatitisckids.freeforums.org. She began online conversations and formed friendships with people who could relate to her struggle to help her son.

Almost exactly a year ago, Elijah began treatment. The Richardses say he is the youngest person undergoing treatment for hepatitis C in North Carolina. While Elijah's treatment originated at UNC Hospitals in Chapel Hill, most of the hands-on efforts come from his mother. Elijah takes antiviral medicines twice a day, and Lana Richards gives her son a once-a-week injection of a chemotherapy medication. Sometimes, she's up all night with him when he's feeling sick.

It is never easy for her, injecting this cheerful little boy with a medication with side effects that sometimes make him very ill.

"I always hesitate,'' she said, "but he always makes me feel better.''

The treatment has taken a toll on Elijah. His blood platelet count is low, and he is battling severe anemia. But if the treatment works - and they won't know that until about six months after his treatment is complete - then Elijah will be considered free of the disease.

That's where the gift of the globe comes in. More than 20 people, most of whom the Richards family knows only from the Internet, banded together and purchased the globe to send to him. A gesture of hope and kindness from all over the world. Elijah can look at those spinning continents and know the locations of all the people who are thinking of him and hoping for the best for him.

They wanted Elijah to know that, all over the world, people are pulling for and praying for this little pioneer. This little hero.

Community news editor Kim Hasty can be reached at hastyk@fayobserver.com or 486-3591.

Source

The Little Dragon Slayer ... Takara's Story

The Little Dragon Slayer

Takara's Story

Takara was daignosed with hepatitis C geno type 1b in June of 2009. Our world as we know it stopped. With the news of Takara having Hep C came the devestating knowledge of how she contracted Hep c, through me, her mother vertical transmission. One may ask why would you have a child knowing you had Hep C? The answer simple. I had just found out I had this virus prior to finding out I was pregnant.

We were informed there was a 3% chance Takara would be infected with the virus. The doctors advised to have her tested at about 2 years of age. We tried several times to have her blood drawn and it wasn't until she was 4 years old before we had a non problematic blood draw which confirmed our worst fear. Takara had Hep C.

Takara's pediatrician reffered us to a infectious disease specialist, who told us he could not treat her. That children are not treated until they are at least 18 years of age. That there was not an approved treatment for children. This answer simply was not acceptable. I began educating myself, searching the internet, making many phone calls and leaving many messages. weeks turned into months. I prayed, searched and prayed some more. I was led to a Pediatric Liver Specialist at UCLA. Dr Susan McDiarmid, 300 miles away and she treated children.

Before Takara could start treatment she needed a liver biopsy. This was to determin the condition of her liver and aid in dosage strength of the medication. Takara started treatment on Feb. 5 2010. It has been almost a year that she has been on treatment. Takara's treatment is over seen by Dr McDiarmid at UCLA, however her medication must be administerd at home. I give her Rebetol (anti viral medication) twice daily and a weekly injection of Pegasys (chemotherapy medication). Takara must also get regular blood draws to monitor her counts. This medicine combination can make, and has made Takara very sick many times. There have been many nights I have been up with her just trying to comfort her. It is not easy to give my little princess medicine, I know will make her sick. Being on treatment for almost a year now has taken a toll on her. Takara has been battling loss of appetite, weight loss, rage, and insomnia to name just a few.

On top of all this Takara tries to carry on her daily routine. She attends all day kindergarten, which she looks forward to and enjoys greatly- most days.

I have met families from all over the world online in my search for knowledge, on how to battle and cope with these dangerous side effects. Families that have supported Takara in her fight against Hep C, some by purchasing from her website I set up for her, and others by praying and sharing valuable information.

It is for this reason, on Takara's last day of treatment in Feb., we are going to present Takara with a Mova Globe. We will show to Takara, all the locations of the families who have been, and still are supporting and praying for her.

Even though Takara's treatment will officially end this Feb. It will be a new begining for her. They call Hep C the "Dragon" and even as her fight with the dragon comes to an end, it will be another 6 months before we will know if treatment was a success for our little Dragon Slayer.

Jenell Chow

Direct Antiviral Agents for Hepatitis C – New Developments

Lange Christian Markus, Sarrazin Christoph, Zeuzem Stefan

European Gastroenterology & Hepatology Review, 2010;6(1):70–7

PDF download article

Abstract
Numerous directly acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection are currently under development. The final results of phase II clinical trials that evaluated the most advanced compounds – telaprevir and boceprevir – indicate that the addition of these NS3/4A protease inhibitors to pegylated interferon-alpha (pegIFN-α) and ribavirin strongly improves the chances of achieving a sustained virological response (SVR) in treatment-naïve HCV genotype 1 patients and in prior non-responders and relapsers. However, monotherapy with DAAs frequently results in the selection of resistant quasi-species and viral breakthrough and is therefore not suitable. Generally, NS5B polymerase inhibitors have a lower antiviral efficacy than protease inhibitors, and their ability to improve SVR rates remains to be established. Future research should elaborate on whether an SVR can be achieved with combination therapies of DAA agents without IFN-α; in addition, DAAs targeting genotypes other than HCV genotype 1 should be evaluated.

Keywords
Directly acting antiviral agents (DAAs), specifically targeted antiviral therapy for hepatitis c (STAT-C), protease inhibitor, polymerase inhibitor, hepatitis C, antiviral therapy, viral resistance, drug resistance

Disclosure: Christian Markus Lange has no conflicts of interest to declare. Christoph Sarrazin is a clinical investigator, consultant and/or a member of the speaker’s bureau of Abbott, BMS, Boehringer Ingelheim, Falk, Gilead, Merck, Novartis, Roche, Siemens, Tibotec and Vertex. Stefan Zeuzum is a clinical investigator, consultant and/or a member of the speaker’s bureau of Abbott, Anadys, BMS, Boehringer Ingelheim, Gilead, HGS, Merck, Novartis, Roche, Tibotec and Vertex.

Received: 7 May 2010 Accepted: 29 June 2010 Citation: European Gastroenterology & Hepatology Review, 2010;6(1):70–6

Correspondence: Stefan Zeuzem, Klinikum der JW Goethe-Universität Frankfurt am Main Medizinische Klinik I, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. E: zeuzem@em.uni-frankfurt.de

The odds of achieving a sustained virological response (SVR) in patients with chronic hepatitis C with a therapy of pegylated interferon-alpha (pegIFN-α) and ribavirin are still too low, particularly in patients infected with hepatitis C virus (HCV) genotypes 1 or 4.1–4 Therefore, intensive efforts have been made to develop directly acting antiviral agents (DAAs) against HCV.5–12 Many of these DAAs are currently in phase I–III development and will significantly change treatment options for HCV infection in the near future. The most advanced compounds are telaprevir and boceprevir, which are both inhibitors of the HCV NS3 protease and have been shown to significantly enhance SVR rates in HCV genotype 1 patients when applied in addition to pegIFN-α and ribavirin.13–15

NS3/4A Protease Inhibitors

NS3/4A protease inhibitors can be divided into two chemical classes: macrocyclic inhibitors and linear tetra-peptide α-ketoamid derivatives. Ciluprevir has a macrocyclic structure and was the first protease inhibitor evaluated in patients with chronic hepatitis C. Ciluprevir, as well as subsequently developed NS3/4A protease inhibitors of both molecular classes, strongly inhibited HCV replication during monotherapy, but also frequently caused the selection of resistant mutants, which may be followed by viral breakthrough.12,16–18 Although the development of ciluprevir was stopped because of serious cardiotoxicity observed in an animal model, the proof of principle was provided for successful suppression of HCV replication by NS3/4A inhibitors in patients with chronic hepatitis C. Subsequent studies have shown that the frequency of resistance development against protease inhibitors can be vastly reduced by the additional administration of pegIFN and ribavirin. Telaprevir and boceprevir are the most advanced NS3/4A protease inhibitors, and are currently in phase III evaluation.

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Keywords:
Directly acting antiviral agents (DAAs), specifically targeted antiviral therapy for hepatitis c (STAT-C), protease inhibitor, polymerase inhibitor, hepatitis C, antiviral therapy, viral resistance, drug resistance

Source

Hepatitis C: In 2011, a predictive marker for response to therapy

Public release date: 5-Jan-2011

Contact: Matthew Albert
albertm@pasteur.fr
33-670-010-396
INSERM (Institut national de la santé et de la recherche médicale)

Scientists at Inserm and Institut Pasteur have performed biomarker discovery on patients being treated for chronic hepatitis C infection. Their work, published in The Journal of Clinical Investigation, demonstrates that the plasma levels of the protein IP-10 predict, prior to treatment initiation, the efficacy of treatment with pegylated-interferon and ribavirin. Based on these results, the scientists have developed a prognostic test. Commercialization is anticipated in 2011, and will help inform physicians of the chances that patients will respond to standard treatment or if instead they will require new therapeutic cocktails (e.g., inclusion of protease inhibitors).

Importantly, hepatitis C is the leading cause of primary liver cancer (hepatocellular carcinoma) and it remains an important cause of liver failure due to fibrosis and cirrhosis. This infectious disease represents a major public health problem, with greater than 170 million cases worldwide. The World Health Organization estimates 3 to 4 million new cases per year and considers the virus a " viral time bomb" due to the long term sequella of infection.

Currently, there is no approved vaccine available and approximately 80% of individuals infected by the virus develop chronic disease, a risk factor for cirrhosis, liver failure, liver cancer as well as other medical complications (e.g., diabetes).

For the past ten years, treatment has been based on the use of type I interferon given in combination with the anti-viral ribavirin. While effective, it results in a cure for only 50% of patients. Moreover, treatment is long (24 – 48 weeks), and it results in severe side effects (e.g., depression, anemia).

It is in this context that the Inserm and Institut Pasteur sponsored research lab of Dr. Matthew Albert, in close collaboration with the Liver Disease Unit headed by Prof. Stanislas Pol, evaluated plasma biomarkers to define predictors for patients' response to treatment.

With the help of the Centre for Human Immunology at Institut Pasteur, the investigators involved have performed a prospective study. They identified the protein IP-10 as a prognostic biomarker – elevated in those patients for whom treatment was ineffective. This observation was paradoxical as IP-10 is considered a pro-inflammatory molecule, which should have facilitated migration of activated T cells to the liver, the exact cell types responsible for viral immunity. In fact, what was discovered is that the IP-10 had been catabolized and it was a truncated form present in the HCV patients. Strikingly, the short form of IP-10 is an antagonist and inhibits T cell recruitment. Thus, it is suggested that the antagonist form of IP-10 is responsible for the failure to respond to treatment in the 50% of patients who do not benefit from pegylated-interferon / ribavirin treatment.

The investigators worked in close collaboration with an American company, Rules Based Medicine, Inc., who will develop a diagnostic test to distinguish the different forms of IP-10 as a simple blood test. This test will be a significant step towards the improved management of patients with HCV as well as other chronic inflammatory diseases.

###

This scientific work was conducted under the direction of Matthew L. Albert, MD PhD, Mixed Institut Pasteur / Inserm Research Unit; and Stanislas Pol, MD PhD, Univerisity of Paris, Descartes and Institut Cochin. Financial support was provided by the ANRS and promotion of the study was taken by Inserm Medical.

To know more:

Source

Evidence for chemokine antagonisms in human infected chronically with Hepatitis C Virus.
Armanda Casrouge, Jérémie Decalf, Mina Ahloulay, Cyril Lababidi, Hala Mansour, Anaïs Vallet-Pichard, Vincent Mallet, Estelle Mottez, James Mapes, Arnaud Fontanet, Stanislas Pol and Matthew L. Albert.

Journal of Clinical Investigation.

and the related news article

Chemokine antagonism in chronic hepatitis C virus infection.
Edgar D. Charles and Lynn B. Dustin

Journal of Clinical Investigation.

Contact information

Matthew Albert
Unité mixte Institut Pasteur / Inserm
Email : albertm@pasteur.fr
Tel : +33 6 7001 0396

Stanislas Pol
Unité 1016 « Institut Cochin »
Service Hépatologie, Hôpital Cochin
Email : stanislas.pol@cch.aphp.fr

Source

LSM detects undiagnosed chronic liver disease

Published date :24-Dec-2010

MedWire News: Study findings show that liver stiffness measurement (LSM) can detect undiagnosed chronic liver disease in apparently healthy individuals, with the added benefit of a 100% positive predictive value for cirrhosis screening.

"So far, liver biopsy has been the gold standard for the assessment of fibrosis in patients with chronic liver disease," say Dominique Roulot (Avicenne Hospital, Bobigny, France) and co-authors.

"However, in cases of suspicion of non-alcoholic fatty liver disease (NAFLD), liver biopsy is difficult to recommend for apparently healthy patients with normal liver tests, because of its possible complications," they add.

A total of 1190 individuals from the general population, aged 45 years or older, attending for a medical check-up participated in the current study. All patients received LSM, in addition to laboratory tests and medical examinations. Those who scored over 8 kPa on the LSM were referred to a liver unit for further investigations.

Overall, 94 (8.5%) patients had a LSM >8 kPa, including nine patients with a LSM >13 kPa. The researchers note that although LSM values were normal in 4% of patients with perturbed liver tests, these tests came back as normal in 43% of patients with LSM >8 kPa.

NAFLD and alcoholic liver disease (ALD) were diagnosed as the likely causes of chronic liver disease in 52 and 20 patients, respectively. Hepatitis B and C were diagnosed in nine patients, and primary biliary cirrhosis in one patient.

Liver biopsy results confirmed that all of the nine patients with LSM >13 kPa had liver cirrhosis due to ALD or chronic hepatitis B/C. The remaining 18 biopsies showed liver fibrosis in all patients except one who presented with isolated steatosis.

Factors significantly associated with a LSM >8 kPa included being aged 57 years or older, having a body mass index ≥30 kg/m2, elevated waist circumference, diabetes, alanine aminotransferase ≥40 UI/l, and γ-glutamyltranspeptidase ≥45 UI/l.

The researchers say the findings suggest that "a relatively high percentage of liver diseases remain undiagnosed in apparently healthy individuals, and that LSM might contribute to referring these patients to hepatologists."

They conclude in the journal Gut: "If future studies determine that the superior positive predictive value of LSM can be achieved at an acceptable cost, compared with common screening methods, LSM might represent a first-line procedure for the mass screening of liver disease in the general population."

MedWire (http://www.medwire-news.md/) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

Source

Study Finds That A Certain Type Of HIV Reduces Breast Cancer Risk Among HIV-Infected Women

By Meerat Oza and Courtney McQueen
Published: Jan 4, 2011 5:03 pm

Results of a recently published study have shown that women infected with a certain type of HIV may have a significantly lower risk of breast cancer compared to women with other strains of HIV, possibly because this type of HIV effectively targets and kills breast cancer cells.

The study authors stated that the results need to be confirmed by additional studies, but may explain results showing women with HIV are at lower risk for breast cancer than women without HIV.

HIV is often associated with increased rates of several types of malignant cancers, such as Kaposi’s sarcoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, cervical cancer, and anal cancer.

However, studies have shown that women with HIV may be at decreased risk of breast cancer. Between 1980 and 2002, the risk of breast cancer was found to be 31 percent lower in HIV-infected women as compared to uninfected women.

Researchers have speculated that this may be because a type of cell protein that HIV sometimes uses to infect immune system cells is also found on the surface of breast cancer cells.

In order to infect healthy white blood cells, HIV binds to certain proteins on their surface, called CCR5 or CXCR4. Most HIV, especially early in infection, uses CCR5 for infection. However, later in infection HIV will sometimes switch to using CXCR4 or a combination of the two proteins.

One hypothesis for why HIV-positive women may be at reduced risk for breast cancer is that the CXCR4 protein is also found on the surface of breast cancer cells. This protein is not found on normal breast cells and may be used by the cancer cells to grow and spread. Scientists have shown that in the laboratory, HIV that binds to breast cancer cells kills them.

If this hypothesis is correct, then women with HIV that uses the protein CXCR4 for infection should be at lower risk of developing breast cancer.

To test their hypothesis, the researchers in this study identified 23 HIV-infected women who had breast cancer and compared them to 69 HIV-positive women without breast cancer who were of similar age.

Results showed that only 9 percent of the women with breast cancer had CXCR4-dependent HIV, compared to 28 percent of the women without breast cancer.

Further analysis revealed that women with CXCR4-dependent HIV were only 10 percent as likely to have breast cancer as women infected with CCR5-dependent HIV.

Menopause was the only other factor that affected the risk of developing breast cancer. CD4 (white blood cell) count, viral load (amount of HIV in the blood), antiretroviral therapy regimen, ethnicity, and other lifestyle factors such as use of alcohol or contraceptives did not correlate with risk.

The researchers concluded that CXCR4-dependent HIV has a protective effect against breast cancer in women, and they speculated that CXCR4-dependent HIV may account for the lower risk of breast cancer in women with HIV.

They suggested that their findings could lead to new methods for trying to combat breast cancer.

Since the study was small, the researchers noted that their results will need to be confirmed by further studies with larger groups of women.

Also, while they presume the lower risk of breast cancer arises from CXCR4-dependent HIV infecting and killing breast cancer cells, they suggested further study on the exact mechanism by which CXCR4-dependent HIV protects against breast cancer.

For more information, please see the study in PLoS One.

Source

Anadys Pharmaceuticals Initiates Phase IIb Study of ANA598 in HCV Patients

SAN DIEGO, Jan. 4, 2011 /PRNewswire/ -- Anadys Pharmaceuticals, Inc. (Nasdaq: ANDS) announced today that it has initiated the planned Phase IIb study of ANA598 in combination with pegylated interferon and ribavirin. The protocol for the study has been cleared by the United States Food and Drug Administration (FDA) and Health Canada. Patient screening has begun and patient dosing is expected to commence within the next several weeks. In the study ANA598 will be tested in both treatment-naive patients and treatment-experienced patients who failed a prior course of therapy with interferon and ribavirin. ANA598 is the Company's direct-acting antiviral, or DAA, being developed for the treatment of hepatitis C.

"We are excited to initiate this Phase IIb study of ANA598," said James L. Freddo, M.D., Anadys' Senior Vice President, Drug Development and Chief Medical Officer. "By establishing safety and efficacy in a greater number of patients, including those who have failed prior HCV treatment, we hope to position ANA598 as a highly attractive HCV agent ready for Phase III development."

Phase IIb Protocol Design

In the study, approximately 200 chronically infected genotype 1 hepatitis C patients are expected to receive ANA598 200 mg twice a day (bid) in combination with Pegasys® (peginterferon alfa-2a) and Copegus® (ribavirin, USP) (a current standard of care, or SOC) with a loading dose of 800 mg bid on day 1, while approximately 66 patients are to receive placebo and SOC. Enrollment is expected to include approximately equal numbers of treatment-naive patients and patients who have failed a prior course of SOC, including difficult to treat prior null-responders. The primary endpoint of the study is Sustained Virological Response 24 weeks after patients conclude all treatment, known as SVR24. Anadys is conducting the study at sites within and outside the United States.

Naive Arm

Approximately 100 treatment-naive HCV patients are expected to receive ANA598 in combination with SOC and 33 treatment-naive HCV patients are to receive placebo plus SOC. Treatment duration for naive patients will be response-guided; patients who achieve undetectable levels of virus at Week 8 and maintain undetectable levels of virus will be scheduled to conclude all treatment at Week 28. For naive patients with detectable virus at Week 8 dosing with ANA598, or placebo, and SOC is planned to continue through Week 48. The Company expects to receive Week 8 antiviral response data by the end of the second quarter of 2011, Week 12 antiviral response data in the third quarter of 2011 and Week 24 antiviral response data in the fourth quarter of 2011.

Treatment-Experienced Arm, Including Prior Null Responders

Approximately 80 patients who were partial responders during, or relapsers after, a prior course of therapy with SOC alone are expected to receive ANA598 in combination with SOC, and 33 corresponding patients are to receive placebo plus SOC. Additionally, approximately 28 prior null responder patients are to receive ANA598 in combination with SOC. All treatment-experienced patients who receive ANA598 are scheduled to receive triple combination therapy for 48 weeks. For the treatment-experienced patients, the Company expects to receive Week 12 antiviral response data in the third quarter of 2011 and Week 24 antiviral response data in the fourth quarter of 2011.

About Anadys

Anadys Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to improving patient care by developing novel medicines for the treatment of hepatitis C. The Company believes hepatitis C represents a large unmet medical need in which meaningful improvements in treatment outcomes may be attainable with the introduction of new medicines. Anadys has initiated a Phase IIb study of ANA598, the Company's DAA, added to current standard of care for the treatment of hepatitis C. The Company is also preparing to resume clinical development of ANA773, the Company's oral, small-molecule inducer of endogenous interferons that acts via the Toll like receptor 7, or TLR7, pathway in hepatitis C.

Safe Harbor Statement

Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to, references to (i) expectations regarding the timing for commencing patient dosing in the ANA598 Phase IIb study; (ii) the goal of establishing safety and efficacy in a greater number of patients, including those who have failed prior HCV treatment; (iii) the hope to position ANA598 as a highly attractive HCV agent ready for Phase III development; (iv) the scheduled trial design for the Phase IIb study; and (v) Anadys' expectations regarding the timing of receipt of data from the study. Such forward-looking statements involve known and unknown risks, uncertainties and other factors, which may cause Anadys' actual results to be materially different from historical results or from any results expressed or implied by such forward-looking statements. For example, the results of preclinical and early clinical studies may not be predictive of future results, and Anadys cannot provide any assurances that ANA598 will not have unforeseen safety issues, will have favorable results in ongoing or future clinical trials or will receive regulatory approval. In addition, Anadys' results may be affected by competition from other biotechnology and pharmaceutical companies, its effectiveness at managing its financial resources, its ability to enter into transactions around its product candidates, its ability to successfully develop and market products, difficulties or delays in its non-clinical studies or clinical trials, difficulties or delays in manufacturing its clinical trials materials, the scope and validity of patent protection for its products, regulatory developments and its ability to obtain additional funding to support its operations. Risk factors that may cause actual results to differ are more fully discussed in Anadys' SEC filings, including Anadys' Form 10-Q for the quarter ended September 30, 2010. All forward-looking statements are qualified in their entirety by this cautionary statement. Anadys is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.

Pegasys® and Copegus® are registered trademarks of Hoffman-La Roche Inc.

SOURCE Anadys Pharmaceuticals, Inc.

Source

NYC Department Of Health Releases H.I.V. PSA (GRAPHIC VIDEO)

First Posted: 01- 4-11 10:34 AM
Updated: 01- 4-11 10:34 AM
 
The NYC Department of Health, which recently has made a name for itself by publicizing startlingly graphic public service announcements, has release a new ad about H.I.V.
 
The tag is "it's never just H.I.V." and the video, which resembles an NBC drama promo, goes on to explain how the virus can lead to other terrible diseases like osteoporosis or dementia.

But the video, which shows only men and flashes graphic illustrations of broken bones, and even documentation of anal cancer, is striking some as far too aggressive a campaign.

The New York Times reports that the ad is dividing health experts and gay activists alike. Those like Larry Kramer, the founder of the AIDS activist group Act Up, think the commercials are effective. "This ad is honest and true and scary, all of which it should be," he told the Times. "H.I.V. is scary, and all attempts to curtail it via lily-livered nicey-nicey 'prevention' tactics have failed."

Others think the message is exploitative and unnecessarily graphic.

"We know from our longstanding H.I.V. prevention work that portraying gay and bisexual men as dispensing diseases is counterproductive," said Marjorie Hill, chief executive ofGay Men's Health Crisis. "Studies have shown that scare tactics are not effective."

Source

Exhausted by Illness, and Doubts

By DAVID TULLER
Published: January 3, 2011

Chronic fatigue syndrome causes a host of debilitating symptoms: profound exhaustion, disordered sleep, muscle and joint pain and severe cognitive problems, among others. But what causes the syndrome itself

Since the first cases in the United States were identified in the 1980s, scientists have been divided over that question. Some have suspected that one or more viral infections are likely to play a central role.

But many other researchers — not to mention relatives, friends, employers, doctors and insurers of the million or more Americans estimated to suffer from the illness — have dismissed it as stress-related, psychosomatic or simply imaginary.

Now recent back-to-back announcements have highlighted both the volatility of the issue and the ambiguity of the science, and have alternately heartened and dismayed patients.

On Dec. 14, an advisory panel suggested that the Food and Drug Administration ban blood donations by people with a history of C.F.S., as the illness is often called. The goal was to prevent the possible spread of viruses that two high-profile studies had linked to the condition.

But then, on Dec. 20, the journal Retrovirology published four papers suggesting that key findings in those studies could have resulted from laboratory contamination.

The F.D.A. is not required to accept the opinion of its advisory panel. Yet patients still hailed the recommendation as a sign that their illness was being taken seriously.

“When an F.D.A. panel suggests that patients with C.F.S. not donate blood, that’s going to impact the way doctors think about it,” said Mary Schweitzer, a former history professor at Villanova, who has frequently written about living with the illness. Dr. Schweitzer said she has been unable to work for 16 years because of the syndrome, which was diagnosed after she suffered from a series of flulike illnesses.

The studies that concerned the F.D.A. had reported that people with the syndrome, which is also called myalgic encephalomyelitis or myalgic encephalopathy in Europe, showed higher rates of infection with the virus XMRV or others from the same category, known as MLV-related viruses. (These viruses are all relatives of mouse leukemia viruses, some of which can infect species other than mice; their role in human disease, if any, remains poorly understood.)

But several other research teams in the last year have found no connection between chronic fatigue syndrome and these viruses, although none tried to replicate the exact methods used by researchers who reported an association.

The new papers in Retrovirology reported that contamination of tissue samples or other laboratory items with mouse DNA or viral genetic material could lead to false positive results for XMRV, and by extension other MLV-related viruses, specifically when using polymerase chain reaction technology. The technique rapidly produces millions of copies of genetic segments, so even minute traces of genetic contamination can skew results.

“Our conclusion is quite simple: XMRV is not the cause of chronic fatigue syndrome,” said the senior author of one of the studies, Greg Towers, a professor of virology at University College London, in a statement released by Wellcome Trust Sanger Institute, the British research center that co-sponsored it.

Other scientists and advocates for patients have sharply criticized such certainty as unwarranted, noting that the Retrovirology papers themselves expressed their findings in more cautious terms. The critics agree that contamination can be a serious issue when using polymerase chain reaction technology. But the new papers, said Eric Gordon, a doctor in Santa Rosa, Calif., who treats many patients with the illness, do not evaluate other strategies besides P.C.R., as the technique is known, for detecting the MLV-related viruses, like testing for an immune response and culturing the viruses in cell lines.

“The articles make the point that P.C.R. doesn’t work that well for these viruses, and then they act like that disproves the whole idea,” said Dr. Gordon.

XMRV was first identified in 2006 and has been detected in prostate cancer patients in some studies. It was linked to chronic fatigue syndrome in October 2009 in a paper in the journal Science by researchers from the Whittemore Peterson Institute for Neuro-Immune Disease at the University of Nevada, Reno, the National Cancer Institute and the Cleveland Clinic.

The researchers relied on P.C.R. technology to show that about two-thirds of patients but less than 4 percent of control subjects harbored XMRV. Using other technologies, however, they also documented an antibody response in some chronic fatigue syndrome patients, and reported that XMRV in human blood could infect other human cell lines.

In a statement responding to the new papers in Retrovirology, Judy A. Mikovits, director of research at Whittemore Peterson and the senior author of the Science study, said her team took extensive steps to rule out P.C.R. contamination and also focused on other approaches to finding XMRV. “Nothing that has been published to date refutes our data,” she said.

Even some specialists stumbled over the meaning of the new findings. Vincent Racaniello, a professor of microbiology at Columbia not involved in the research, apologized on his Virology Blog for having stated that it was likely to spell “the beginning of the end” for the proposed connection between the viruses and chronic fatigue syndrome.

After reviewing the issue more thoroughly, he wrote, he realized that the new studies “show that identification of XMRV can be fraught with contamination problems, but they do not imply that previously published studies are compromised.” He added, “If I had difficulties interpreting these papers, how would nonscientists fare?”

Federal agencies have come down on different sides of the issue. In a paper published in The Proceedings of the National Academy of Sciences in August, researchers from the National Institutes of Health and the F.D.A. found a link between the fatigue syndrome and MLV-related viruses (although not specifically XMRV). In contrast, a study from the Centers for Disease Control and Prevention was among those not reporting a link.

Federal health officials have organized two research efforts to resolve the inconsistencies, determine whether XMRV and MLV-related viruses are possible human pathogens, and identify reliable ways to detect them. Patients hope the increased attention will quickly lead to research on treatments, including clinical trials of H.I.V. drugs, some of which have been shown in lab studies to inhibit the replication of XMRV.

The unsettled situation has created a quandary for patients with chronic fatigue syndrome and the doctors who treat them. Some patients are seeking to be treated with H.I.V. drugs, which doctors can legally prescribe even though the F.D.A. has not approved them for that purpose.

Many doctors and researchers say it is too early to prescribe the drugs for chronic fatigue because of possible side effects, like bone marrow suppression, gastrointestinal problems and liver or kidney dysfunction, among others. But Michael Allen, a writer and a former psychologist in San Francisco who has been disabled for more than 15 years, said he wouldn’t hesitate to try the medications if he found out he was positive for an MLV-related virus.

“It feels patronizing when the medical establishment says the side effects are too risky and we should keep waiting,” he said. “What that says to me is they have no idea whatsoever how sick people like me have been with this disease.”

Source

Related: The Lingering Mystery of Chronic Fatigue Syndrome

Hepatitis A warning issued for those who received Communion on Christmas at N.Y. church

By Mary Forgione
Tribune Health
January 4, 2011, 12:21 p.m.

Communion and hepatitis A are rarely mentioned in the same sentence. But health officials in New York are concerned that parishioners at a Long Island church who took Communion on Christmas Day may have been exposed to hepatitis A. Church-goers in attendance that day are being urged to get a hepatitis A vaccine shot.

A statement issued Monday by the Nassau County Health Department to Our Lady of Lourdes Church in Massapequa Park said: "Individuals may be at risk if they received Communion during the 10:30 a.m. and 12 noon masses on December 25, 2010."

Hepatitis A is a virus transmitted by eating or drinking something that has been contaminated with the feces of an infected person. It’s rarely fatal, unlike other forms -- Hepatitis C in particular -- of the liver disease.

Here are symptoms to look for from the Centers for Disease Control and Prevention: fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, clay-colored bowel movements, joint pain and jaundice.

And the treatment? There really isn't any, though some who become dehydrated from nausea or vomiting may require hospitalization. Read more from the CDC about hepatitis A. And the Foundation for Digestive Health and Nutrition explains the different forms of hepatitis here.

Now, don't let any of this be an excuse to skip church.

Source

EU drugs agency launches new guidelines for HIV testing in injecting drug users

Download the PDF here

Guidelines for testing HIV, viral hepatitis and other infections in injecting drug users

A manual for provider-initiated medical examination,
testing and counselling

EMCDDA, Lisbon, November/December 2010, Source: European Monitoring Centre for Drugs and Drug Addiction

EMCDDA: European Monitoring Centre for Drugs and Drug Addiction ...

Aims to provide reliable information on drugs and drug addiction in the EU. Provides online reports databases about drug usage and anti-drug programs. www.emcdda.europa.eu/

EMCDDA, your reference point on drugs in Europe

The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) was established in 1993. Inaugurated in Lisbon in 1995, it is one of the EU's decentralised agencies.

The EMCDDA exists to provide the EU and its Member States with a factual overview of European drug problems and a solid evidence base to support the drugs debate. Today it offers policymakers the data they need for drawing up informed drug laws and strategies. It also helps professionals and practitioners working in the field pinpoint best practice and new areas of research.

"The EMCDDA estimates that 30Ð50% of HIV positive IDUs in Europe are unaware of being infected. It also estimates that around 50% of IDUs (varying between countries from 10% to 90%) are infected with viral hepatitis (notably hepatitis C), which can lead to severe liver disease and premature death."

More injecting drug users should undergo tests for HIV, viral hepatitis and other infections such as tuberculosis, says the EU drugs agency (EMCDDA). In new guidelines published today on the eve of World AIDS Day, the agency describes how, in this group, the uptake of testing is still low in many European countries (1).

Infectious diseases are among the most serious health consequences of injecting drug use and can lead to significant healthcare costs. The new guidelines recommend a strategy to increase testing uptake, both in Europe and beyond, that would ensure earlier treatment for injecting drug users (IDUs) and would lower the risk of infection spreading to the wider population.

IDUs are vulnerable to a range of infectious diseases due to a variety of risk behaviours and underlying conditions, such as poor hygiene, homelessness and poverty. The EMCDDA estimates that 30Ð50% of HIV positive IDUs in Europe are unaware of being infected. It also estimates that around 50% of IDUs (varying between countries from 10% to 90%) are infected with viral hepatitis (notably hepatitis C), which can lead to severe liver disease and premature death.

Commenting today, EMCDDA Director Wolfgang Gštz said: 'It is crucial that those infected are aware of their condition so that they can protect their partners and access the appropriate care and treatment. We encourage service providers and healthcare professionals to take a more proactive approach and ensure that clients at the highest risk of contracting drug-related infections are offered testing on a regular basis. Until now, timely diagnosis and treatment of infectious diseases has often been too low a priority among professionals in contact with drug users'.

Today's manual provides guidance at a practical level, proposing a series of standard tests to be undertaken regularly on a voluntary and informed basis. Among these are serology tests for HIV, hepatitis (A, B, C, D) and other sexually transmitted infections; general blood tests; and tests for tuberculosis. For high-risk IDUs, these tests should be considered annually, or even bi-annually. The guidelines also offer a package of prevention, primary care and referral routines in relation to IDUs and infections.

The guidelines recommend that health providers initiate examination, testing and counselling in IDUs in a variety of healthcare settings (e.g. primary healthcare; special health services for IDUs; low-threshold service centres visited by IDUs; rehabilitation centres; dedicated sexually transmitted infections clinics and prison healthcare facilities). Developed in collaboration with European experts on drug-related infectious diseases, the guidelines are now being distributed across the European Union and globally. They are intended to be of use to thousands of service providers, and may potentially benefit hundreds of thousands of IDUs.

Summary:

Infectious diseases are among the most serious health consequences of injecting drug use and can lead to significant healthcare costs. Injecting drug users are vulnerable to a range of infectious and communicable diseases through a variety of risk behaviours, and because of underlying conditions such as poor hygiene, homelessness and poverty. There is a recognised need for guidance on providing IDUs with a medical examination and testing for HIV, viral hepatitis and several other infections on a regular basis. In addition, improving testing uptake in this group would benefit epidemiological surveillance and monitoring as carried out at the national and international level.

These guidelines are accompanied by a recommended package of prevention and primary care in relation to injecting drug users and infections. Treatment and other specialist care are not discussed in detail but are dealt with by indicating referral to appropriate services.

A thorough medical examination, testing and counselling of IDUs should include:

testing for infections;
post-test counselling;
prevention counselling;

Basic recommended tests
The tests that should be included in a standard offer to all IDUs in provider-initiated routine
medical examinations are-
Serology testing for:
· HIV
· hepatitis A
· hepatitis B
· hepatitis C
· hepatitis D (if evidence of chronic or recent hepatitis B);
· syphilis.

Hepatitis C

When to refer: All IDUs with a positive antibody test and a positive PCR should be followed up by a repeated test after three to six months, and if the test is still positive, should be considered for eradication therapy. Liver function status is important in the evaluation of the need for medication therapy.

Specific guidelines exist for the treatment of hepatitis C at national and European level (Hepatol, 1999). It is important to note that although some guidelines still exclude active IDUs or IDUs on opioid substitution treatment from viral treatment, study results indicate that IDUs can be successfully treated and may avoid reinfection (Hepatol, 1999; Reimer et al., 2005).

Training and ongoing supervision and monitoring of healthcare providers carrying out routine medical examination, testing and counselling with IDUs is required for the successful implementation of the service. Training programmes for personnel should be developed

Source

Insulin resistance predicts re-treatment failure in an efficacy study of peginterferon-α-2a and ribavirin in HIV/HCV co-infected patients

Download the PDF here

Jnl of Hepatology Dec 2010

"Baseline IR (insulin resistance) was strongly associated with virological response. This study demonstrates that a proportion of HIV/HCV co-infected patients respond to HCV re-treatment. The best outcome is achieved in patients with baseline HOMA-IRφ2. Calculating baseline HOMA-IR may be a useful tool when considering re-treatment. Future studies are needed to confirm these findings and determine if improvement of HOMA-IR prior to starting HCV therapy increases SVR rates. The impact of IR on SVR requires further study in patients receiving direct-acting antiviral agents as they are soon to become part of standard HCV treatment......This is the largest prospective study of HCV re-treatment in the population of HIV/HCV co-infected patients conducted so far. In this study, re-treatment with pegIFN-α-2a plus weight-based RBV led to a SVR rate of 15%. The strongest predictor of failure to achieve SVR was IR and the highest SVR rate of 35% was in patients with HOMA-IR<2. This is the first study to examine IR as a possible predictor of SVR during re-treatment of HIV/HCV co-infected patients. IR appears to predict SVR better than steatosis or cirrhosis. As such, these data provide important insight into the management of hepatitis C in co-infected persons who failed to respond to prior therapy."

From Jules of NATAP: At AASLD Vertex reported insulin resistance did not impact SVR, I would feel more comfortable with this finding in monoinfection after a study in coinfection:

No Impact of Insulin Resistance on Antiviral Efficacy of ...
Nov 3, 2010 ... No Impact of Insulin Resistance on Antiviral Efficacy of Telaprevir-based Regimen in HCV Genotype 1 Treatment-naïve Patients: Subanalysis of ...
www.natap.org/2010/AASLD/AASLD_76.htm

Marie-Louise C. Vachon 1 Corresponding Author Information email address, Stephanie H. Factor 2, Andrea D. Branch 1, Maria-Isabel Fiel 3, Maribel Rodriguez-Torres 4, Norbert BrŠu 5 6, Richard K. Sterling 7, Jihad Slim 8, Andrew H. Talal 9, Douglas T. Dieterich 1, Mark S. Sulkowski 10

1 Division of Liver Diseases, Mount Sinai School of Medicine, NY, USA
2 Division of Infectious Diseases, Mount Sinai School of Medicine, NY, USA
3 Department of Pathology, Mount Sinai School of Medicine, NY, USA
4 Fundacion de Investigacion de Diego, San Juan, PR, USA
5 Divisions of Infectious Diseases and Liver Diseases, Mount Sinai School of Medicine, NY, USA
6 Veterans Affairs Medical Center, Bronx, NY, USA
7 Division of Liver Diseases, Virginia Commonwealth University Health Systems, Richmond, VA, USA
8 Division of Infectious Diseases, St-Michael's Medical Center, NY, USA
9 Division of Gastroenterology and Hepatology and Center for the Study of Hepatitis C, Weill Cornell Medical College, NY, USA
10 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MA, USA

Background & Aims

Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. The aim of this study is to evaluate the safety and efficacy of pegylated interferon-α-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response, including insulin resistance, and the relationship between insulin resistance and liver histology.

Methods

This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-α-2a and ribavirin for 48weeks. Serum HCV RNA was measured 24weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR>2. Correlations between baseline insulin resistance and steatosis, and/or cirrhosis were determined.

Results

Sustained virological response was achieved in 14/96 (15%) patients. 35% of patients with HOMA-IR<2 (6/17) achieved sustained virological response vs 14% (5/36) of those with HOMA-IR between 2-4, and 7% (3/41) of those with HOMA-IR>4 (p=0.01). In multivariable analysis, insulin resistance and log10 HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95% CI 0.05-0.64, p=0.009, and AOR 0.36; 95% CI 0.14-0.93, p=0.04, respectively]. Steatosis and cirrhosis correlated with insulin resistance (p=0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% of cases, and 2 patients died of unrelated causes.

Conclusions

In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those patients without insulin resistance are significantly more likely to achieve sustained virological response.

Abbreviations: HIV, human immunodeficiency virus, HCV, hepatitis C virus, HRN, hepatitis Resource Network, HCV RNA, hepatitis C virus ribonucleic acid, HOMA-IR, homeostasis model of assessment of insulin resistance, AOR, adjusted odds ratio, CI, confidence interval, HCC, hepatocellular carcinoma, SVR, sustained virological response, PegIFN, pegylated interferon, RBV, ribavirin, IR, insulin resistance, IFN, interferon, HIV RNA, human immunodeficiency virus ribonucleic acid, ART, antiretroviral therapy, ULN, upper limit of normal, Hb, hemoglobin, HbA1c, hemoglobin A1c, TSH, thyroid-stimulating hormone, pEVR, partial early virological response, cEVR, complete early virological response, EOT, end of treatment, IRB, institutional review board, HAI, histology activity index, BMI, body mass index, IQR, interquartile range, OR, odds ratio, SAE, severe adverse event, RVR, rapid virological response, ACTG, AIDS Clinical Trials Group, SOCS3, suppressor of cytokine signaling 3, IRS-1, insulin receptor substrate 1, STAT-1, signal transducers and activators of transcription 1

Introduction

Co-infection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) affects an estimated 10 million people worldwide. HCV-related liver disease is now a leading cause of death among HIV-infected patients [1], [2]. Successful treatment of HCV is associated with reduced liver-related complications, including liver decompensation, hepatocellular carcinoma (HCC), and liver-related mortality [3], [4].

The goal of HCV treatment is to achieve sustained virological response (SVR), defined as undetectable serum HCV RNA 24weeks after the end of treatment. The current standard of care is 48weeks of peginterferon-α (pegIFN) and ribavirin (RBV; fixed dose for HCV genotypes 2 and 3, and weight-based for HCV genotypes 1 and 4). However, SVR is achieved in less than half of HIV/HCV co-infected patients in both initial and re-treatment of HCV. In initial HCV treatment, the combination of pegIFN and weight-based RBV has lead to SVR in 22-35% of patients with HCV genotypes 1 and 4 [5], [6] and 53-72% of patients with HCV genotypes 2 and 3 [6], [7]. Despite the high rate of failure of initial HCV treatment regimens, few studies have been done on re-treatment of HCV in co-infected non-responders. The studies that have been published were small and reported overall SVR rates of 16-31% [8], [9], [10], [11]. In addition, predictors of SVR in re-treatment have not been well studied.

HIV/HCV co-infected patients, who had failed to respond to a previous course of HCV treatment, were enrolled in an open-label, phase IIIb study (Hepatitis Resource Network (HRN)-004) to evaluate safety, tolerability, and efficacy of pegIFN-α-2a and RBV in re-treatment. In addition, we prospectively evaluated predictors of SVR including baseline insulin resistance (IR). Finally, we examined the relationship between baseline IR and liver histology (steatosis and cirrhosis).

Discussion

This is the largest prospective study of HCV re-treatment in the population of HIV/HCV co-infected patients conducted so far. In this study, re-treatment with pegIFN-α-2a plus weight-based RBV led to a SVR rate of 15%. The strongest predictor of failure to achieve SVR was IR and the highest SVR rate of 35% was in patients with HOMA-IR<2. This is the first study to examine IR as a possible predictor of SVR during re-treatment of HIV/HCV co-infected patients. IR appears to predict SVR better than steatosis or cirrhosis. As such, these data provide important insight into the management of hepatitis C in co-infected persons who failed to respond to prior therapy.

Non-response to HCV treatment is common in HIV/HCV co-infected patients treated with pegIFN and RBV. Our population had a high prevalence of factors known to predict non-response to HCV treatment. Specifically, there was a high prevalence of men, African American race, Latino ethnicity, prior treatment non-responders as opposed to relapsers, HCV genotype 1 infection, high HCV RNA levels, steatosis, cirrhosis, and IR.

Baseline IR was strongly associated with virological response. These data are consistent with prior retrospective studies at the initial course of HCV treatment in co-infected patients. Among 238 co-infected patients treated with pegIFN-α-2b and RBV, Cacoub and colleagues reported that a HOMA-IR score>2.5 was a negative predictor of SVR [17]. In a cohort of 134 co-infected patients, Ryan et al. similarly reported that a HOMA-IR score >3.8 was a negative predictor of SVR [18]. A third retrospective study of 74 HIV/HCV co-infected patients reported that a HOMA-IR >3.0 was a negative predictor of rapid virological response (RVR) [19]. RVR is achieved when serum HCV RNA is below the limit of detection at week 4 and is a known correlate of SVR [20]. One study found that IR was not associated with response to pegIFN (α-2a and α-2b) and RBV in treatment-naive HIV/HCV co-infected patients [21]. However the results appeared to show a negative dose-response relationship between baseline HOMA-IR score and SVR rate. These results may be explained by differences in patient samples, in terms of both sample size and patient characteristics. The patients in the study by Merchante et al. were younger (median age 40 vs 48years), had lower BMI scores (median 22.9 vs 25.8), and were all Caucasians (100% vs 28% of our patients). Furthermore, they were HCV treatment naïve, had less advanced liver disease (15% cirrhosis vs 27% of our patients), and a lower prevalence of IR. Twenty-nine percent had HOMA-IR scores>4, compared to 44% in our population.

In our study, co-infected patients with HOMA-IR<2 had a SVR rate of 35% compared to 7-14% in those with higher scores. The 35% SVR rate in patients with HOMA-IR<2 is equivalent to SVR rates achieved in the HIV/HCV co-infected patients undergoing initial treatment. This suggests that calculation of HOMA-IR prior to treatment may improve the estimate of treatment response.

In HCV mono-infected patients, recent studies evaluated the impact of insulin sensitizing agents on SVR at the time of starting pegIFN and RBV treatment in patients with IR. Two showed positive results in defined populations [22], [23], one did not [24]. An ongoing study using pioglitazone prior to pegIFN and RBV therapy is being conducted in HIV/HCV co-infected patients with IR who were non-responders to prior HCV treatment (ACTG 5239).

There is biological data supporting the association between IR and treatment response. Insulin diminishes the ability of IFN to inhibit HCV replication in a replicon model at insulin levels similar to those seen in patients with IR [25]. Elevated levels of suppressor of cytokine signaling 3 (SOCS3) in liver biopsies predict IFN treatment failure [26], [27], [28]. Some evidence suggests that SOCS3 down-regulates both insulin receptor substrate 1 (IRS-1), a key component of the insulin signaling pathway [29], and signal transducers and activators of transcription 1 (STAT1), a key component of IFN signaling [30]. This literature suggests that induction of SOCS3, which is reported to occur in cells carrying the HCV core gene [29], [30], might contribute to both IR and IFN treatment failure in patients.

Our statistical models suggest that IR is more significantly associated with response to HCV re-treatment in HIV-infected patients than is steatosis or cirrhosis. Similar to previous studies, this study demonstrates a correlation between IR and both steatosis and cirrhosis [31], [32]. Previous studies have found steatosis and cirrhosis to be negative predictors of response to HCV treatment in some patient populations [32], [33], [34], [35], [36]. The correlation between IR and steatosis/cirrhosis and their ability to negatively predict treatment response suggest all three may be markers of pathologic changes along a common pathway. With our current technology, IR is the only measure which does not require an invasive procedure and is therefore feasible for widespread use.

While we found baseline HCV RNA to be statistically associated with SVR, we did not find HCV genotype to be associated with SVR. This is not consistent with prior studies [10], [11]. In the study by Labarga et al., HCV genotypes 2 and 3 infection was significantly associated with SVR compared to HCV genotypes 1 and 4, as was RBV plasma trough concentrations at week 4 [11]. The high prevalence of HCV genotype 1 compared to HCV genotypes 2 and 3 in this study may have prevented our ability to find associations. It is also possible that HCV genotype, while a significant predictor of treatment success for initial treatment of HIV/HCV co-infected patients, may not be as significant of a predictor during re-treatment. The low prevalence of patients with prior HCV relapse compared to HCV non-responders is also likely responsible for the lack of association with SVR in this study. However, prior small studies of re-treatment in the population of HIV/HCV co-infected patients have not found prior relapse vs non-response to be significantly associated with SVR [8], [10], [11].

Previous studies on predictors of SVR have often included EVR and total dose of pegIFN and/or RBV as predictors in their univariable and multivariable analyses; we did not. Because EVR almost always (98-100%) predicts SVR, EVR is likely along the causal pathway to SVR and therefore a measure of outcome not exposure. PegIFN-α-2a and weight-based RBV were given to all participants up to week 20 and virological status at week 20 determined further treatment. Thus, the total dose of pegIFN-α-2a and RBV was, in part, determined by the risk factors at baseline. Similar to EVR, medication dose in this study is a measure of outcome.

This study, with numerous strengths, expands the current literature but has some limitations. The most important strength is the prospective collection of data using standardized tools. Our study is limited by its sample size and the homogeneity of the patients in sex, age, and HCV genotype. The homogeneity of the population, especially the high prevalence of patients with HCV genotype 1 infection and HOMA-IR above 2, may have contributed to the strong relationship we found between baseline IR and SVR in this study. At the time the study was conducted, IL28B polymorphisms analyses were not performed. This information may have influenced our study results.

This study demonstrates that a proportion of HIV/HCV co-infected patients respond to HCV re-treatment. The best outcome is achieved in patients with baseline HOMA-IRφ2. Calculating baseline HOMA-IR may be a useful tool when considering re-treatment. Future studies are needed to confirm these findings and determine if improvement of HOMA-IR prior to starting HCV therapy increases SVR rates. The impact of IR on SVR requires further study in patients receiving direct-acting antiviral agents as they are soon to become part of standard HCV treatment.

Patients and methods

Patients

Patients were recruited at 10 centers in the United States from August 2002 to June 2005. Eligible patients were co-infected with HIV and HCV and had either relapsed or not responded to prior IFN-based treatment. Chronic HCV infection was defined as a positive HCV antibody test for at least 6months and detectable serum HCV RNA. HIV-related criteria included patients with either (i) CD4+ T-cell count<100 cells/mm3 and HIV RNA level<25,000IU/ml, or (ii) CD4+ T count100 cells/mm3 and any HIV viral load. Patients were required to be on stable antiretroviral therapy (ART) or off ART for at least 4weeks prior to the screening visit. Prior IFN-based treatment was defined as IFN-α monotherapy or IFN-α and RBV combination therapy administered for at least 12weeks and discontinued for at least 4weeks before the screening visit. Prior non-response was defined as a <2-log10 decrease in HCV RNA at week 12 or detectable HCV RNA at week 24 during HCV treatment. Prior relapse was defined as detectable HCV RNA after cessation of treatment in a patient who had undetectable HCV RNA at the end of treatment. A liver biopsy showing features consistent with chronic HCV infection was required within 18months prior to study entry.

Exclusion criteria were decompensated liver disease (ascites, bleeding varices, or encephalopathy), other causes of liver disease (steatosis and steatohepatitis were not excluded), prothrombin time3 s, bilirubin>20% above the ULN, albumin<3.0g/dl, hemoglobin (Hb)φ11g/dl, white blood cell countφ3000/mm3, absolute neutrophil countφ1250/mm3, platelet countφ70,000/mm3, fasting blood glucose>115mg/dl in non-diabetic patients, HbA1c>8.5% in diabetic patients, serum creatinine1.5mg/dl, abnormal TSH value, alpha-fetoprotein100ng/ml, hemoglobinopathies, alcohol and/or drug abuse within 1year of entry (active intravenous drug users were excluded), severe psychiatric disease, hypersensitivity to IFN or RBV, pregnancy or breastfeeding, and persons unwilling to use contraception during the study period.

Results

Baseline characteristics

Of the 102 patients enrolled, 6 did not receive study medication and 96 were included in the study (Table 1). Median age was 48years (Interquartile range (IQR)=44-53). The group was 84% male, 42% Latino, 29% African American, and 28% Caucasian. Of the 96 patients, 81 (85%) were infected with HCV genotype 1. Twenty-one (22%) patients had a past history of intravenous drug use and none were active users.

Of the 94 patients with available baseline fasting insulin and glucose levels, 77 (82%) had a HOMA-IR>2; 36 (38%) had a HOMA-IR between 2 and 4; and 41 (44%) had a HOMA-IR>4. Steatosis was present in 53 (55%) of the liver biopsies and cirrhosis was present in 26 (27%). Of the 96 patients, 92 (96%) had a CD4+ T-cell count >200, 81 (84%) were on ART and 67 (70%) had undetectable HIV RNA.

Efficacy outcomes

Of the 96 patients who received at least one dose of the study drug, 37 (39%) experienced EVR. Twelve (13%) had pEVR and 25 (26%) had cEVR. An EOT response was achieved in 30 (31%) patients and SVR was achieved in 14 (15%) (Fig. 1). The negative predictive value of EVR to achieve SVR was 100%. The positive predictive value of EVR (partial and complete) to achieve SVR was 38%.

In the univariable analyses of possible predictors of SVR, IR was negatively associated with SVR [odds ratio (OR) 0.21; 95% CI 0.06-0.73, p=0.02] (Table 1). In multivariable logistic regression, IR and baseline log10 HCV RNA were negatively associated with SVR [adjusted odds ratio (AOR) 0.17; 95% CI 0.05-0.64, p=0.009, and AOR 0.36; 95% CI 0.14-0.93, p=0.04, respectively]. The interaction between IR and HCV RNA was not significant.

A sub-analysis including only patients with HCV genotype 1 infection (n=81) was performed. Out of 81 patients, 10 (12%) achieved SVR. In multivariable analysis, HOMA-IR>2 was the only independent negative predictor of SVR (AOR 0.16; 95% CI 0.04-0.67, p=0.01). The African American race and Latino ethnicity were correlated with the presence of IR, but were not significant predictors of SVR when analyzed in the multivariable model.

Role of baseline IR and SVR

The matched, nested case-control analysis included 81 patients, with 14 cases matched to between 1 and 6 controls. In both univariable and multivariable analyses, IR was negatively associated with SVR (AOR 0.13; 95% CI 0.03-0.55, p=0.006).

When looking at SVR in relation to the HOMA-IR score divided into 3 categories,<2, 2-4, and >4, there was a significant negative dose-response relationship between percent SVR and HOMA-IR: 35% (6/17) in HOMA-IR<2, 14% (5/36) in HOMA-IR between 2 and 4, and 7% (3/41) in HOMA-IR>4 (p=0.01, chi-square test for trend) (Fig. 2).

Relationship between baseline IR and liver histology

IR was correlated with steatosis (r=0.22, p=0.02) and cirrhosis (r=0.23, p=0.03). Steatosis was present in 47/77 (61%) patients with IR, compared to 5/17 (29%) patients without IR (p=0.02). Cirrhosis was present in 25/77 (32%) patients with IR, compared to 1/17 (6%) patients without IR (p=0.03). When looking at the HOMA-IR score divided into 3 categories, <2, 2-4, and >4, there was a positive dose-response relationship between both percent steatosis and HOMA-IR (p=0.02, chi-square test for trend), and percent cirrhosis and HOMA-IR (p=0.03, chi-square test for trend) (Fig. 3).

Using the multivariable logistic regression models with SVR as the outcome, log10 HCV RNA as a covariate, and steatosis or cirrhosis substituted in for IR, the models for steatosis and cirrhosis had larger -2log likelihood values indicating that these models were less precise in predicting SVR (Table 2).

A sub-analysis including only patients without cirrhosis (n=70) was performed. Out of 70 patients without cirrhosis, 13 (19%) achieved SVR. In multivariable analysis, HOMA-IR>2 was negatively associated with SVR (AOR 0.22; 95% CI 0.06-0.89, p=0.03). Baseline log10 HCV RNA was also significantly associated with SVR (AOR 0.37; 95% CI 0.14-0.98, p=0.046) in this analysis.

Safety and tolerability

The most common adverse events were cytopenias. Anemia with Hb<10g/dl occurred in 13 (14%) patients and severe anemia (Hb<8.5) occurred in 3 (3%). A neutrophil count<750/mm3 occurred in 74 (77%) and a neutrophil count<500/mm3 occurred in 48 (50%). A platelet count<50,000cells/mm3 occurred in 5 (5%) patients. RBV dose reduction was required in 18 (19%) patients during treatment, most frequently due to anemia. PegIFN-α-2a dose reduction was required in 25 patients (26%) during treatment, most frequently due to neutropenia. There were no incidents of opportunistic infections, episodes of hepatic decompensation, or development of HCC. There were two deaths in the study patients both of which were unrelated to study medications.

Overall, 23 (24%) patients discontinued treatment. Thirteen discontinuations were due to adverse events. There were 8 discontinuations due to severe adverse events (SAEs), all within the first 24weeks (3 severe anemia, 2 suicidal ideation, 1 hyperglycemia, 1 diarrhea and fever, and 1 rhabdomyolysis).

Study design

Patients received 180μg pegIFN-α-2a subcutaneously every week plus weight-based RBV (Pegasys® and Copegus®, Roche Laboratory, Nutley, NJ, USA), regardless of HCV genotype (800mg/day for <65kg; 1000mg/day for 65kg and φ85kg; 1200mg/day for>85kg). A complete medical history, physical examination, and laboratory tests were taken at the baseline visit. Additional data were collected at weeks 2, 4, 8, 12, 16, 20, 24, 36, and 48 during treatment and 24weeks after the end of treatment. Unlike traditional treatment, patients who did not achieve a 2-log10 drop in HCV RNA at week 12 did not discontinue treatment. The decision to discontinue treatment was made at week 24 based on the week 20 HCV RNA result. Patients with a detectable HCV RNA level at week 20 were considered treatment failures and were diverted to a maintenance study arm to be discussed elsewhere. Patients with undetectable HCV RNA at week 20 were continued on treatment for a total of 48weeks.

Partial early virological response (pEVR) was defined as a decrease of at least 2-log10 HCV RNA from baseline but with detectable HCV RNA at week 12. Complete EVR (cEVR) was defined as undetectable HCV RNA at week 12. End of treatment (EOT) response was defined as undetectable serum HCV RNA at week 48. Successful treatment was defined as sustained virological response (SVR) (an undetectable HCV RNA at 24weeks after the end of treatment).

Safety and tolerability were assessed by the evaluation of adverse events, adherence, and discontinuation of study drugs at weeks 2, 4 and every 4weeks through week 48 then at weeks 4, 12, and 24 after the end of treatment. For the management of side effects due to RBV, the initial dose was reduced to 600mg daily until the event responsible for the dosage adjustment was resolved. For management of side effects due to pegIFN-α-2a, the initial dose was reduced by half until the event responsible for the dosage adjustment was resolved. Growth factors for anemia and neutropenia were used at the individual investigator's discretion.

The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. The protocol and consent form were approved by a central institutional review board (IRB) and IRBs of participating sites. Informed consent was obtained from each patient included in the study.

Laboratory tests

Quantification of serum HCV RNA was performed using the AMPLICOR HCV MONITOR® Test, version 2.0 (Roche Molecular Diagnostics, Branford, CT, USA). The detection limit was 600IU/ml. Quantification of serum HIV RNA was performed using the AMPLICOR® HIV-1 MONITOR UltraSensitive Test (Roche Molecular Diagnostics, Branford, CT, USA). The limit of detection was 48 copies/ml. To determine fasting serum levels of glucose and insulin, patients fasted overnight for at least 12h prior to blood collection. Serum samples were let to stand for 15min to allow clotting, centrifuged at full speed for 15min, frozen in cryovials, and shipped the same day for analysis. Serum glucose was determined using the VITROS® 950 test (Ortho Clinical Diagnostics, Rochester, NY, USA) and insulin level was determined using the Immulite® 1000 assay (Siemens Healthcare Diagnostics Deerfield, IL, USA). All laboratory tests were performed at a central laboratory (Consolidated Laboratory Services Van Nuys, CA, USA).

The homeostasis model of assessment of insulin resistance (HOMA-IR) was calculated using the equation described by Matthews et al.: HOMA-IR=fasting insulin (mU/ml)xfasting glucose (mmol/l)/22.5 [12]. Fasting glucose was measured in mg/dl and thus every value was multiplied by a factor of 0.055 before being used in the formula. A person with a HOMA-IR value above 2 was defined as having IR consistent with previous studies [13], [14].

Liver pathology

Liver specimens, which were obtained 18months prior to study entry, were fixed in formalin and embedded in paraffin before they were stained with hematoxylin-eosin and Masson Trichrome. Each was reviewed by a single pathologist at the central site (M-I F) who was unaware of the patient's clinical and biological data. The Ishak-modified histology activity index (HAI) classification scale was used to analyze the biopsy specimens for necroinflammation (range 0-12), and fibrosis (range 0-6). Cirrhosis was defined as a fibrosis score of 5-6 [15]. Steatosis was graded by percentage of liver parenchyma with fat-containing hepatocytes (0 for none; 1 for 1-32%; 2 for 33-67%; and 3 for >67% [16].

Statistical analysis

To determine the efficacy of the treatment, the percentage of patients achieving SVR was calculated. Consistent with previous studies on the efficacy of pegIFN and RBV, the denominator included all patients who received at least one dose of the study drug. Treatment failures included patients who were lost to follow up, discontinued treatment per study protocol at week 24, discontinued treatment due to adverse events, did not achieve SVR, withdrew from the study, or died.

To evaluate predictors of SVR, host characteristics (age, sex, race, body mass index (BMI), baseline HOMA-IR), HCV-related characteristics (HCV genotype, log10 HCV RNA, and non-response versus relapse to prior HCV therapy), HIV-related characteristics (CD4+ T-cell count, HIV RNA, and current use of ART), and liver pathology (steatosis and cirrhosis) were evaluated. First, univariable analyses were done using Chi-square, Fisher's Exact test, Student's t-test or Mann-Whitney, as appropriate, with SVR as the outcome. Second, variables with p-valueφ0.20 in univariable analysis were evaluated using forward and backward multivariable logistic regression to identify variables significantly associated with SVR.

To further study the relationship between IR and SVR, we conducted a post hoc matched, nested case-control analysis. Cases were those who achieved SVR and controls were those who did not. Cases and controls were placed into strata based on baseline HCV RNA and were matched on HCV genotype within each strata. McNemar's test was used for univariable analysis to identify significant associations between SVR and possible predictors. Conditional logistic regression with SVR as the outcome was used to determine whether IR was a statistically significant predictor of SVR.

To determine if IR was correlated with steatosis and/or cirrhosis, Spearman's rank correlation was used. To determine the best predictor of SVR among these three, we used the multivariable logistic regression model obtained above with SVR as the outcome, all variables found to be statistically associated with SVR as covariates, and we substituted IR, steatosis, and cirrhosis as the main predictor. We compared the -2log likelihood values for each model to identify which model had the best fit.

All analyses were done using SPSS Statistics 17.0 (Chicago, IL, USA) or Epi Info Version 6 (CDC, Atlanta, GA, USA). The Cox regression function was used for the conditional regression analysis. A p-value<0.05 (two-sided) was considered significant in all analyses.

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Lower Recurrence Rate for HCC Treated With Resection Than Radiofrequency Ablation

By: DENISE NAPOLI, Internal Medicine News Digital Network

01/03/11

Although percutaneous radiofrequency ablation and surgical resection for small hepatocellular carcinomas have similar survival rates, ablation patients have a higher rate of cancer recurrence, compared with surgical resection patients, reported Dr. Hung-Hsu Hung and colleagues in the January issue of Clinical Gastroenterology and Hepatology.

Dr. Hung, of Taipei (Taiwan) Veterans General Hospital and the National Yang-Ming University, also in Taipei, looked at 419 consecutive patients who underwent radiofrequency ablation (RFA) or surgical resection (SR) at the hospital in 2002-2007. All patients had no more than three small (5 cm or less) liver tumors without extrahepatic metastasis (Clin. Gastroenterol. Hepatol. 2011 January [doi:10.1016/j.cgh.2010.08.018]).

In all, 190 patients underwent RFA and the remaining 229 underwent SR to treat their liver cancer. Patients who chose SR were on average slightly younger (60 years vs. 67 years; P less than .001). This was expected, given the invasive nature of the surgery.

Additionally, the authors found that there was a higher proportion of patients with chronic hepatitis B in the SR group than in the RFA group (59.8% vs. 46.3%; P = .004), whereas chronic hepatitis C was more common in the RFA group (44.7% vs. 26.6%; P less than .001).

This was also an expected finding, because in chronic HBV infection, hepatocellular carcinomas tend to occur at a younger age, the researchers wrote.

Regarding survival, 83 patients had died after a median follow-up of more than 42 months. "Among the 190 patients [who] underwent RFA, 41 (21.6%) died during the follow-up period; 97 (51.1%) were alive with regular visits" until Jan. 31, 2010, and the remaining 52 (27.4%) were lost to follow-up sometime before 2010.

In comparison, there were 42 deaths (18.3%) among the SR group, with 120 patients known to be alive through Jan. 31, 2010 (52.4%), and the remaining 67 patients (29.3%) lost to follow-up.

"The cumulative overall survival rates at 1, 2, 3, and 5 years were 97.3%, 92.2%, 88.2%, and 79.3% in the SR group and 96.6%, 86.7%, 77.3%, and 67.4% in the RFA group, respectively," a significant difference in univariate analysis (P less than 0.009), wrote the authors.

However, after controlling for the older age and comorbidities of the RFA group in multivariate analysis, the authors found that RFA was not an independent risk factor associated with poor survival.

Next, the authors looked at factors associated with cancer recurrence. Overall, 244 patients had experienced tumor recurrence at a median of 14.5 months following RFA or SR.

"The cumulative recurrence rates at 1, 2, 3, and 5 years were 17.4%, 30.5%, 43.9%, and 59.1% in the SR group and 37.4%, 54.1%, 71.0%, and 79.5% in the RFA group, respectively (P less than .001)," they reported.

As with survival, that translated to a significantly higher univariate risk of recurrence among RFA patients (hazard ratio, 2.05; 95% confidence interval, 1.58-2.65). When assessed in a multivariate analysis, RFA was still significantly associated with cancer recurrence (HR, 1.95; 95% CI, 1.48-2.57; P less than .001).

The finding of equal survival but greater recurrence among RFA patients persisted in a third propensity analysis, which employed nearest-neighbor one-to-one matching of 84 patients in each group in terms of age, sex, tumor size, tumor number, platelet counts, hepatitis status, and several other parameters.

The only subgroup for which RFA was equal to SR in terms of both survival and tumor recurrence was patients with solitary hepatocellular carcinoma less than 2 cm in size, known as "very early small HCC (Barcelona Clinic Liver Cancer stage 0)" tumors.

According to the authors, their study "highlights the importance of close surveillance after local ablation therapy." Additionally, the authors concluded that RFA may be a good alternative to surgical resection for BCLC stage 0 HCC, although prospective study is needed.

Dr. Hung and colleagues disclosed no conflicts of interest related to this study.

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The CDC HIV/Hepatitis/STD/TB Prevention News Update

January 3, 2011

 

National News 

• TEXAS: "Teen Parenting Programs Get Real: Students Listen When Peers Talk About Legal Responsibility, Money, Diapers"

International News 

• EGYPT: "No Sex Education, Please, We're Arab"
• PHILIPPINES: "HIV Infections Rising in Some Areas of Philippines, Warns UN Official" 

Medical News

• CANADA: "Methadone Use in Relation to Hepatitis C Virus Testing in British Columbia" 
• THAILAND: "An Exploration of Factors Influencing Adherence to Highly Active Antiretroviral Therapy (HAART) Among People Living with HIV/AIDS in Northern Thailand" 

Local and Community News

• PENNSYLVANIA: "Philadelphia's Condom Contest"

News Briefs

• NEW YORK: "HIV Deaths Fall Below 1,000"
• CALIFORNIA: "Volunteers Sought to Lead HIV Support Groups"

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