The Natural History of Acute Hepatitis C

From Alimentary Pharmacology & Therapeutics

The Natural History of Acute Hepatitis C

Clinical Presentation, Laboratory Findings and Treatment Outcomes

R. Loomba; M. M. Rivera; R. McBurney; Y. Park; V. Haynes-Williams; B. Rehermann; H. J. Alter; S. K. Herrine; T. J. Liang; J. H. Hoofnagle; T. Heller

Authors and Disclosures

Posted: 05/05/2011; Alimentary Pharmacology & Therapeutics. 2011;33(5):559-565. © 2011 Blackwell Publishing

Abstract and Introduction

Abstract

Background Acute hepatitis C has variable modes of presentation and frequently results in chronic infection. Its optimal management has yet to be defined.
Aim To establish natural history and complications of treatment of acute hepatitis C.
Methods Data from all patients presenting with acute hepatitis C to the National Institutes of Health between 1994 and 2007 were reviewed.
Results Twenty-five patients were identified. Symptoms were reported by 80% and jaundice by 40%. Aminotransferase levels and hepatitis C virus (HCV) RNA levels fluctuated greatly; 18% of patients were intermittently negative for HCV RNA. Five patients recovered spontaneously whereas 20 developed chronicity or received interferon-based therapy during the acute phase. Among 15 patients treated during the acute phase with peginterferon with or without ribavirin for 24 weeks, all became HCV RNA negative within 4–8 weeks, and all except two (HIV-positive) achieved a sustained virological response. Side effects (particularly psychiatric) were common and limited treatment in 30%.
Conclusions Among 25 patients with acute HCV infection, fluctuating illness was common and spontaneous recovery occurred in only 20%. Anti-viral treatment with a 24-week course of peginterferon and ribavirin was highly effective, but marked by frequent and severe side effects.

Introduction

Chronic infection with the hepatitis C virus (HCV) is now the leading cause of liver-related morbidity and mortality in the US and accounts for an estimated 10 000 deaths yearly.^[1] In contrast, acute HCV infection has become uncommon, new cases having decreased markedly over the last 15 years to a currently historic low level.^[2] Nevertheless, cases of acute hepatitis C continue to occur and eventuate in chronic infection in 70–80% of cases. Among patients who develop chronic hepatitis C, between 20% and 30% develop cirrhosis over the subsequent two to three decades; and likely a higher proportion thereafter.^[1–6]

Clearance of HCV during the acute phase of infection is typically associated with appearance of a vigorous T-cell response against multiple HCV epitopes; whereas evolution to chronicity is associated with poor T-cell responses that are limited in scope and depth.^[7,8] Jaundice and young age are clinical factors associated with an increased likelihood of clearance of HCV.^[9] In an individual case, however, there are no features that reliably predict recovery. Even serial testing for HCV RNA can be unreliable as levels of virus may fluctuate widely during the acute course and become transiently undetectable, only to be followed by its reappearance and persistence.

The high rate of chronicity of acute hepatitis C has led to studies of therapy. In a study from Germany, a 24-week course of standard alpha interferon monotherapy was reported to result in sustained viral clearance in 98% of persons treated during the acute phase of hepatitis C.^[10] This response rate was higher than would be expected to occur spontaneously and far higher than a similar regimen would achieve in chronic hepatitis C. Subsequent studies, however, have reported somewhat lower rates of response (71–94%) even using similar cohorts.^[9,11–15]

Acute hepatitis C has been a focus of natural history and immunological studies at the Clinical Center of the National Institutes of Health during the last 15 years. Because of publications on the success of therapy of acute hepatitis C in 2001, subsequent patients were offered therapy during the acute phase of disease using the combination of peginterferon α-2a and ribavirin for 24 weeks. This study describes the clinical course of 25 patients with acute hepatitis, some relevant virological features and responses to anti-viral therapy

Methods

Between 1994 and 2007, 25 patients with acute hepatitis C were evaluated and followed by the Liver Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases at the Clinical Center of the National Institutes of Health. Patients were enrolled in clinical research protocols that were approved by the NIDDK NIH Institute Review Board and all patients gave written informed consent. Patients were treated with a 'standard of care approach' and results were analysed retrospectively. Results of immunological studies and virological outcomes in a subset of seven patients of this cohort have been published.^[16] The diagnosis of acute hepatitis C was based upon the detection of HCV RNA in serum and either: (i) documented anti-HCV seroconversion; (ii) documented exposure to HCV followed by elevations in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) to above five times the upper limit of the normal range (ULN) within the subsequent 6 months, or; (iii) probable exposure to HCV followed by acute elevations in ALT or AST levels to above 10 times the ULN within the subsequent 6 months. In addition, patients were enrolled in this study only if they had no other obvious cause of acute liver disease (drug-induced liver injury, hepatitis A, hepatitis B, acute alcoholic hepatitis) and gave written informed consent.

All patients underwent an initial history and physical examination and had a battery of blood tests including routine liver tests (ALT, AST, alkaline phosphatase, albumin, direct and total bilirubin and prothrombin time) as well as serological tests for acute hepatitis A (IgM anti-HAV) and hepatitis B (HBsAg and IgM anti-HBc). Patients were tested for HCV RNA by qualitative polymerase chain reaction (Cobas Amplicor, Version 2.0; Roche Diagnostics, Branchburg, NJ, USA; lower limits of detection of 100 IU/mL) and for anti-HCV using ELISA (Abbott, North Chicago, IL, USA). Selected samples were tested for HCV RNA levels using the Cobas Amplicor Hepatitis C Virus Monitor Test, Version 2.0 (Roche Diagnostics; lower limit of detection 600 IU/mL). HCV genotyping was performed by hybridisation (InnoLipa; Innogenetics, Ghent, Belgium). Other testing included complete blood counts, erythrocyte sedimentation rate, total immunoglobulin levels, a heterophile test, Rapid Plasma Reagin, routine urinalysis and abdominal ultrasound. Patients were then followed up in the outpatient clinic at 2- to 4-week intervals until either 6 months after treatment ended or having three negative tests for HCV RNA, and at 3- to 6-month intervals thereafter. On each occasion, symptoms of hepatitis were assessed using standardised questionnaires and visual analogue scales.
The time of documented or suspected exposure to HCV was used to calculate incubation period as well as time to seroconversion and recovery. In cases that patients did not recall the specific date of exposure, an approximation was made, based upon best recall.

Prior to 2001, anti-viral therapy was not recommended until at least 6 months after exposure and documentation that chronic hepatitis C had been established. However, because therapy failed in a high proportion of chronically infected patients and because of reports of high success rates following treatment early in HCV infection,^[10] treatment was subsequently recommended once HCV RNA was found present for at least 16 weeks after exposure. Patients who wanted to be treated earlier than recommended were allowed to begin therapy if HCV RNA was still detectable in serum. From 1994 to mid-2001, patients (n = 5) were treated with standard interferon in a dose of 3 million units subcutaneously three times weekly with or without oral ribavirin (1000 mg daily if body weight <75 kg, and 1200 mg daily if ≥75 kg) for 24 or 48 weeks. After mid-2001 and the availability of pegylated forms of interferon, patients (n = 15) were treated with peginterferon (either alpha-2a, 180 μg weekly or alpha-2b, 1.5 μg/kg weekly) and ribavirin (1000 or 1200 mg daily) for 24 weeks only. Patients were followed up for at least 24 weeks after completing treatment to document whether a sustained virological response (SVR) had been achieved.

Results

Baseline Characteristics

Between January 1994 and June 2007, 25 patients (16 females and 9 males) met the diagnostic criteria for acute hepatitis C and were followed up. A total of 17 patients were Caucasians (three Hispanic in ethnicity and one with Native American parentage), six African Americans and two Asians (Table 1). The mean age at time of exposure was 43 years (range: 20–72 years). Genotype distribution included: 72% genotype 1, 4% genotype 2 and 4% genotype 3; in the remaining 20%, the genotype could not be determined. The route of infection is summarised and defined in Table 1; the presumed source of infection was needle-stick injury in nine (36%), sexual exposure in five (20%), occupational exposure in three (12%), medical procedures in three (12%), razor sharing in two (8%), injection drug use in two (8%) and was unknown in one (4%) – a patient whose only reported parenteral exposure was a professional manicure 4 weeks before presentation. Time of exposure was determined with certainty in nine patients (needle-stick exposure). Time of exposure was determined within a week in eight patients. In the remaining eight patients, the time of exposure was approximated according to presentation and patient's best recollection.

Most patients (n = 20, 80%) were symptomatic and 10 patients (40%) were jaundiced. The most common symptoms were fatigue (68%), dark urine (60%), abdominal pain (60%), low-grade fever and chills (44%), loss of appetite (40%), itching (36%), muscle aches (36%), mood disturbances (32%), joint aches (24%), dyspepsia (16%) and diarrhoea, and confusion (8% each). The most common clinical sign was icterus, which was reported in 10 (40%) patients. Two patients developed acute liver failure marked by hepatic encephalopathy and ascites, but both recovered symptomatically and subsequently responded to anti-viral therapy with clearance of HCV RNA. Acne was reported by two patients and maculopapular skin rash by one. The average time from exposure to onset of signs or symptoms was 4 weeks (range: 2.5–8 weeks).
Laboratory testing showed ALT levels greater than 10 times the ULN in 17 patients (70%) and peak bilirubin levels above 2.5 mg/dL in 11 (44%). Prothrombin time elevations occurred in the two patients with encephalopathy and ascites. Anti-HCV seroconversion was documented in 20 patients (80%). The remaining five (20%) of the patients were anti-HCV positive at the time of presentation. The average time from exposure to seroconversion was 9 weeks (range: 6–12 weeks). All patients tested positive for HCV RNA. The mean peak HCV RNA level was 5.3 × 10⁶ copies/mL (range: <600 to 27.8 × 10⁶ copies/mL). During follow-up and while not on therapy, four of 22 patients (18%) who had frequent monitoring of HCV RNA levels were intermittently negative and 15 patients (68%) had >1 log (10-fold) fluctuation in viral levels. The calculated mean difference between the peak and nadir pre-treatment viral levels was 2.2 log₁₀ copies/mL (P < 0.01). Three patients had extreme fluctuations in viral levels with intermittent negativity (Figure 1). In most patients, fluctuations in viral levels were present only during the first 24 weeks after exposure, but these fluctuations continued beyond 24 weeks in at least one patient, and most others were started on treatment before 24 weeks.

Figure 1.

Extreme fluctuations in viral levels in three patients pre-treatment. Levels below 100 IU/mL were reported as negative.

 

Outcomes

Five patients cleared HCV RNA spontaneously and remained HCV RNA-negative on multiple occasions thereafter (range: 4–10) during 4, 13, 24, 31 and 42 months of follow-up. One patient refused follow-up beyond 4 months. The average time to spontaneous loss of HCV RNA was 19.6 weeks (range: 16–24 weeks). The remaining 20 patients (80%) appeared to be developing chronic infection and were eventually treated with an interferon-based regimen. Because of the evolving nature of therapy of hepatitis C, several regimens were used. Five patients received standard interferon alpha-2b (3 million units three times weekly). The initial two patients received interferon monotherapy; while the next three received interferon and ribavirin (1000 or 1200 mg daily). After 2001, patients were offered therapy with peginterferon (either alpha-2a or alpha-2b) and ribavirin. One patient with concurrent human immunodeficiency virus (HIV) infection received peginterferon monotherapy because of concerns over interactions of ribavirin with antiretroviral agents being used (zidovirine and didanosine) and the excellent results reported with interferon monotherapy. Of the 20 patients treated, all except three achieved an SVR and had normal serum ALT levels and no detectable HCV RNA when last seen (mean = 31.7 months, range = 9–79 months after stopping therapy). One patient counted as an SVR received interferon monotherapy 6 months after exposure and relapsed when therapy was stopped, but had a long-term SVR in response to re-treatment with standard interferon and ribavirin. The three patients who did not achieve an SVR included one patient who was treated with standard interferon and ribavirin starting 8 months after exposure who never became HCV RNA negative during therapy and two other patients who were HIV-positive and became HCV RNA negative on peginterferon therapy but then had viral breakthrough and did not have a sustained response (one received peginterferon monotherapy). Thus, the overall SVR rate was 85%. SVR rates were 83% (15/18) for patients with genotype 1, 83% (five of six) among African American patients, but only 33% (one of three) in HIV-positive subjects. One subject was both HIV-positive and the single African American nonresponder. Among the 12 HIV-negative patients treated during the acute phase of illness with the combination of pegylated or standard interferon and ribavirin for 24 weeks, all became HCV RNA negative within 1–8 weeks of initiating therapy (mean = 2.8 weeks) and the SVR rate was 100%.

Side Effects

No patient had an exacerbation of liver disease or worsening of serum ALT levels while on therapy (Table 2). However, typical side effects of interferon and ribavirin were reported in virtually all treated patients and were problematic in many. Psychiatric side effects were particularly troublesome. Selective serotonin reuptake inhibitor (SSRI) prophylaxis was given to 35% of patients, and another 15% initiated SSRI therapy while on treatment in response to depression. One patient had a relapse of injection drug use on therapy. New onset of autoimmune disease occurred in five patients (25%); including two cases of papilitis, and one each of polymyalgia rheumatica, hyperthyroidism and hypothyroidism. Three patients (15%) went on disability while on treatment. Therapy was discontinued early because of side effects in six patients (30%) (after 9–23 weeks), but all six had an SVR. Of the 20 patients treated, one had dose reduction of ribavirin from 1000 to 800 mg because of fatigue. Another patient had a dose reduction of peginterferon to 60 μg weekly because of recurrent ear infection. Both tolerated the rest of their treatment without any further dose reduction and both had an SVR. A third patient had initially started at 3 million IU of interferon three times a week, but subsequently increased dose to 5 million units of interferon three times a week. This was then decreased back to 3 million units of interferon three times a week because of fatigue. This patient also had an SVR.

Discussion

Acute hepatitis C is now uncommon in the US but still presents a challenge in diagnosis, assessment of prognosis and therapy. The 25 patients seen were not representative of cases of acute hepatitis C occurring in the US, in that the source of infection in the majority was medical occupation or needle stick accident. In contrast, in the general population, the major risk factor for acquisition of HCV infection is injection drug use, a risk factor identified in only two of the 25 cases described here. Despite this, the clinical course and outcome of cases did appear to be representative of acute hepatitis C. Spontaneous recovery occurred in only 20% of patients, although the rate of recovery could have been higher, because most patients were started on therapy during the acute phase of infection. This rate of 20% is similar to previously published reports.^[17] Almost half the cases were associated with jaundice and two were severe, fulfilling criteria for acute liver failure. Both of these patients developed mild encephalopathy, ascites and elevations in prothrombin time but did not progress to full hepatic coma and were never listed for liver transplantation. Both patients recovered clinically, but remained HCV RNA positive and were ultimately treated and had an SVR in follow-up. Thus, acute hepatitis C can be severe and protracted, but clinical recovery is common and the major medical concern is not the complications of acute disease, but rather the evolution to chronicity.

A striking finding in monitoring patients during this study was the fluctuating nature of the infection, with marked variation in levels of ALT and AST in association with marked changes in HCV RNA levels. Indeed, several patients had periods during which HCV RNA was undetectable, suggesting that they had recovered. During follow-up, however, HCV RNA and ALT elevations returned. Indeed, two patients were told that they had recovered and were found to be persistently HCV RNA positive only when they returned for routine follow-up several months later. These findings are compatible with earlier studies of post-transfusion hepatitis C and indicate that monitoring of patients should continue for at least 6 months after exposure and that a single normal ALT value or absence of HCV RNA does not reliably indicate full recovery and eradication of virus.
In this series of patients, therapy of acute hepatitis C was highly effective when initiated early in the infection. The first five patients seen were given standard interferon alpha-2b, and for most of them, therapy was not initiated until they were documented to be HCV RNA positive for at least 6 months. Using this approach, however, one patient given interferon monotherapy was a nonresponder and another had repeated viral breakthrough on interferon monotherapy but subsequently had an SVR after a 48-week course of combination therapy. The remaining three responded to interferon and ribavirin combination therapy but two required treatment for 48 weeks as recommended for chronic hepatitis C. After this experience and after publications reporting the success of therapy initiated during the acute phase of illness, patients were advised to start therapy with peginterferon and ribavirin if they remained HCV RNA positive for 16 weeks. Using this approach, 13 of 15 patients had an SVR in response to treatment; the two without an SVR had a transient response and breakthrough and concurrent HIV infection (one receiving peginterferon monotherapy). While the number of patients treated was small, these results suggest that HIV infection but not viral genotype or race may be factors associated with a lower rate of response. While uncontrolled, these results also indicate that the majority of patients with acute hepatitis C can be successfully treated.

Another striking finding in this study was the number and severity of side effects of anti-viral therapy. Anti-viral therapy usually resulted in rapid improvements in serum ALT levels and disappearance of detectable HCV RNA. However, virtually all patients had constitutional side effects and specific adverse events were problematic enough to lead to early discontinuation in 30% of patients. This proportion is much higher than what was seen in an acute hepatitis C 126-case prospective study where only 11% of patients discontinued therapy because of severe side effects.^[18] The frequency of side effects may reflect the focused approach in the presented case series to capturing adverse events and also the patient population, which were often medical personnel. Nevertheless, the severity of side effects is an important reason to embark on therapy only if necessary.

A further important consideration is when to initiate therapy. The decision to recommend waiting for 16 weeks after exposure was a compromise between wanting to avoid therapy of patients who might recover spontaneously and published data to initiate therapy before the disease becomes chronic. However, most patients did not accept this delay in treatment. A recent meta-analysis of acute hepatitis C SVR rates and timing of treatment initiation revealed that the highest response rates were seen when treatment was started at 12 weeks of diagnosis.^[19] It should be noted that the time of diagnosis is distinct from the time of infection. Choosing to start therapy 16 weeks from point of infection may, in fact, be earlier than the 12 weeks presented in the meta-analysis study. Waiting 12 weeks after diagnosis may be later than the optimal time to initiate therapy. It seems to be that waiting until patients present clinical manifestations may be preferred. The question of how to standardise treatment time course still remains to be elucidated.

Chronicity in hepatitis C is generally defined by the presence of infection or detectable HCV RNA for at least 6 months. This definition is helpful but somewhat arbitrary. The transition from acute to chronic HCV infection most likely represents a change in the interaction between the immune system and the viral infection that does not necessarily occur exactly 6 months after onset of infection. In this regard, the striking fluctuations in ALT and HCV RNA levels may be a marker for the acute phase of illness, in that they are usually followed by a relatively stable levels of ALT and viral RNA during chronic infection. The cause of this variability in viral levels and disease activity during acute infection remains unclear, but it appears to be associated with similar fluctuations in CD4⁺ and CD8⁺ T-cell responses to HCV antigens^[16] and thus may reflect active immunological response to virus infection and thus represent an ideal time to add anti-viral treatment to help tip the balance in favour of viral clearance.

As an SVR was achieved in virtually all patients who were treated within 6 months of exposure and did not have concurrent HIV infection, it is possible that a shorter course of therapy or use of lower doses of peginterferon and/or ribavirin might have been as effective. Recent studies from Egypt and Italy suggest that a 12-week course of peginterferon alone may be adequate, particularly if therapy is started early.^[11,12] Indeed, in the current study, 30% of patients stopped therapy early because of side effects, yet still achieved an SVR. An additional reason for an abbreviated course of treatment was the number and severity of side effects. However, the possible advantages of an abbreviated course of therapy must be balanced against the possible consequence of failure of therapy. Patients who fail to respond to treatment or relapse during acute infection may need to be re-treated once the disease is chronic, at which point therapy is likely to be less effective and require longer courses.

Thus, experience in management of acute hepatitis C indicates that the disease can be severe and is likely to result in chronic infection. Initiation of a 24-week course of peginterferon and ribavirin can result in a high rate of ultimate recovery and sustained eradication of virus. Anti-viral therapy, however, has problematic side effects and further studies are needed to define markers that will indicate which patients are unlikely to have a spontaneous clearance of virus and whether more abbreviated courses or lower doses of peginterferon and ribavirin can achieve similar high rates of response.

 

• References
• http://www.medscape.com/viewarticle/741366

Genes and Hepatitis C; Susceptibility, Fibrosis Progression and Response to Treatment

From Liver International

Genes and Hepatitis C

Susceptibility, Fibrosis Progression and Response to Treatment

Manuel Romero-Gomez; Mohamed Eslam; Agustín Ruiz; Marta Maraver

Authors and Disclosures

Posted: 04/28/2011; Liver International. 2011;31(4):443-460. © 2011 Blackwell Publishing

Abstract

Hepatitis C virus contact and infection show three different phenotypes: spontaneous viral clearance (SVC), chronic hepatitis C (CHC) and sustained virological response (SVR) following antiviral treatment. Many factors, including genetics, influence the evolution of these three phenotypes. We performed a literature search (PubMed) up to 31 January 2010 without language restriction to identify relevant studies on genes and hepatitis C. Additional studies were sought by reviewing the reference lists of the identified articles. Meta-analysis (using Meta-disk 1.4) was conducted to evaluate the association of single nucleotide polymorphism (SNP) in the IL28B region and SVR. The candidate gene approach showed strong relationships between human leucocyte antigen class II (DQB1*0301 and DRB1*1101) and SVC. A cirrhosis risk score involving 7 SNPs has been validated recently. The set of odds ratios of studies demonstrated an association between SNP (rs12987960/rs8099917) in the IL28B and SVR in CHC treated with peginterferon plus ribavirin (OR: 4.6; 95% CI: 2.9–7.3). The overall distribution of protective allele correlated with ethnic differences in SVR (Asians, Europeans, Hispanic and Afro-Americans) together with SVC, but not with fibrosis stage or viral load. These polymorphisms did not influence SVR in very-easy-to-treat patients such as genotype 2/3, rapid virological responders or patients with acute hepatitis C. While the genetic fingerprint for fibrosis progression remains elusive, IL28b polymorphism predicts SVC and SVR. However, nearly half of patients achieving SVR did not show favourable genotype. Further genetic signals are warranted to complete the puzzle of factors influencing hepatitis C.

Introduction
Over the past 15 years, several studies have addressed the role of genetic factors in spontaneous clearance, fibrosis progression and response to combined antiviral therapy. Documented evidence indicates that interindividual genome variability contributes considerably to the observed differences in natural resistance or susceptibility to specific micro-organism, to the observed phenotype once infection is established, or to the therapeutic response when the infectious disease is pharmacologically treated. Recently, genome-wide association studies (GWAS) including a large number of single nucleotide polymorphisms (SNP) confirmed the influence of some polymorphisms in the interleukin 28B (IL28B) region on the possibility of achieving viral clearance, either spontaneously or after pegylated interferon alpha+ribavirin (Peg-IFN/RBV) treatment. This genetic marker is a stronger predictor of sustained response than other well-documented factors such as viral genotype, viral load or fibrosis. All these data supported the emerging interest of hepatologists in the influence of genetic factors in hepatitis C virus (HCV). In this review, we analyse the impact of genes on susceptibility, fibrosis progression and sustained virological response (SVR).

Methods
Relevant studies were identified by searching Medline (PubMed) up to 31 January 2010. We searched the literature without language restriction using a combination of the following terms: ('Hepatitis C'[Mesh] OR 'Hepacivirus'[Mesh] OR 'Hepatitis C, Chronic'[Mesh]) AND ('Databases, Genetic'[Mesh] OR 'Genetic Testing [Mesh] OR 'Genetic Association Studies'[Mesh] OR 'Genetic Loci'[Mesh]). To guarantee no loss of specific articles relating genetic factors and susceptibility to HCV infection, or hepatic fibrosis progression, or SVR following IFN treatment, a search combining the terms 'Hepatitis C'[Mesh]' AND 'Genetic Predisposition to Disease'[Mesh] OR 'Liver Cirrhosis'[Mesh] OR 'sustained virological response' was also performed. Additional studies were sought by reviewing the reference lists of the identified articles. Two co-authors separately examined the titles and abstracts. All original human studies concerning the topics of this review were selected for further full-article analysis, provided phenotypes and genotypes were correctly defined. Because the field of hepatitis C genetics remains a topic on which few studies have used prospective designs or had included large sample sizes, it was our intent to include as much information as possible despite some of these data requiring confirmation in better-designed studies. We conducted a meta-analysis that included all published studies reporting odds ratio (OR) or risk ratio that had been calculated by comparing the prevalence of genotype CC (rs12968760) in patients with SVR vs non-SVR. Data were combined using fixed effect (Mantel–Haenszel) as well as random effect (DerSimonian and Laird) models. Random effects were selected when heterogeneity was present.
The phenotypes analysed in the current review were: (a) spontaneous viral clearance (SVC), defined as patients showing positive anti-HCV by EIA 3.0 and repeatedly negative HCVRNA by polymerase chain reaction (PCR); (b) histological fibrosis assessed by Metavir, Scheuer or Ishack index. Fibrosis progression rate was calculated in some studies when the date of infection was known. An index was derived as the fibrosis stage divided by the period of time between infection and liver biopsy. Patients could be classified in cross-sectional analysis as advanced vs non-advanced fibrosis or according fibrosis progression rate as 'faster' or 'slower' fibrosis; (c) SVR was defined as negative HCVRNA at 6 months from the end of therapy.

Genetic Factors and Susceptibility to Hepatitis C

Following acute HCV infection, spontaneous resolution of HCV infection has been reported as being between 10 and 80% of those infected; approximately a quarter of patients with acute HCV spontaneously clear the virus.^[1] Race and gender are the main factors involved in spontaneous clearance, together with clinical presentation (clearance is more often seen after icteric hepatitis), absence of human immunodeficiency virus (HIV) co-infection, rapid decline of HCV RNA and the strength and pattern of hepatitis C-specific CD4 cell responses.^[2] Host factors have been involved in infectious diseases under the paradigm of gene–environmental interaction. To control infectious agents, multicellular organisms have developed an extremely sophisticated defense network, i.e. the immune system, which serves to repel viral and bacterial infections and to avoid pervasive distribution of microorganisms within tissues that may compromise overall hemostasis and survival. Genome-wide RNA interference experiments have revealed a panoply of host genes involved in HCV propagation.^[3] Host genetic factors contribute towards explaining differences in the natural history of several infectious diseases such as leprosy,^[4,5] AIDS,^[6,7] dengue,^[8] malaria^[9] or chronic hepatitis B.^[10] Further, there are specific genomic variants related to the immune system, such as those observed within MAL gene, that can confer on the carriers of these variants a degree of protection against a variety of microorganisms.^[11] HCV infection is not an exception, and the discovery of host factor contributing to HCV pathogenesis will help us to understand host–virus relationships, and to improve our management of the HCV pandemic.

An Update on the Search for Hepatitis C Virus-related Genetic Host Factors

The candidate gene approach has been the most widely used in identifying genetic factors involved in HCV susceptibility. This implies that almost all studies performed to-date are hypothesis driven and that the selections of candidate genes have been based on the knowledge accumulated on HCV lifecycle, or genes involved in the functioning of the immune system. An analysis of the selected candidate genes reveals that investigators have scanned the human leucocyte antigen (HLA) region in detail, as well as cytokines related to natural and acquired immunity such as IFN, tumour growth factor (TGFβ1) and IL pathways. In contrast, other genes related to viral lifecycle have received less attention (see details later).

Candidate Genes from the Human Leucocyte Antigen Region

The HLA region, located at chromosome 6p21, comprises several of genes involved in antigen recognition and host immunity. Alric et al.^[12] originally proposed the contribution of HLA region to HCV risk. Antigen class II DQB1*0301 and DRB1*1101 alleles have been associated with spontaneous clearance of HCV in several independent studies with individuals of different ethnic backgrounds, and supported by meta-analyses.^[13] Indeed, high-resolution genotyping of major histocompatibility (MHC) antigens class I and II of a large multiracial cohort of women from the USA infected by HCV demonstrated that several class I and class II alleles are associated with HCV viraemia.^[14] Although the association between HLA region and SVC seems incontrovertible, the specific variants involved in this genetic association, the exact proteins related to SVC and/or the molecular mechanisms of such variants remain largely unclear. Further, the strong (and long range) linkage disequilibrium (LD) within the HLA region and the co-existence of multiple optimal candidate genes within this DNA segment complicate the positional cloning of true functional variants underlying the observed genetic associations with SVC. For example, it was proposed that one of the contributing genes for this association could be tumour necrosis factor (TNF). TNF locus is located at 6p21.33 within the HLA region between lymphotoxin alpha and beta (LTA and LTB) loci. Overall, TNF is located closer to HLA-G and HLA-B regions than to the HLA-DQ locus and it was originally proposed to play a critical role in immune response to HCV infection.^[15] However, a meta-analysis of 12 independent studies comprising 1395 cases and 1288 controls for the −308A/G marker revealed a slight, and statistically non-significant, effect of this marker for the risk of HCV infection (OR=1.18; P=0.096).^[16] However, because of this weak effect, combined with the observed trend towards association, it cannot be ruled out that TNF variants might contribute to HLA region-SVC phenotype association by acting in concert (additively or epistatically) with other polymorphisms within the HLA region.^[17] Indeed, MHC classes I and II loci are >1.2 megabases away, and the genetic signals observed are probably tracking different functional variants. Individual differences in spontaneous resolution of HCV infection could be explained by the existence of epistasis between HLA region and other unlinked loci. It was hypothesized that the existence of epistasis between MHC class I and killer cell immunoglobulin-like receptor (KIR) genes might modulate the spontaneous clearance of HCV. Notably, homozygous carriers of genotypic combinations of KIR (2DL3/2DL3) and its natural ligand, HLA-C (C1/C1 allotype), are protected against HCV infection (OR for spontaneous resolution=1.71, CI: 1.2–2.42; P=0.003).^[18] Further, this original study also suggested that a therapeutic reduction of inhibitory signals to natural killer might help the host in the spontaneous clearance of HCV. However, studies to replicate the effect of this genotype pair have produced contradictory results, i.e. positive association in some series,^[19,20] and negative in others.^[21] Analyses using larger series and exhaustive meta-analyses are necessary for a definitive view of these interesting findings.

Other Candidate Genes Analysed

Early-on, the existence of genes outside of the HLA region had been hypothesized in relation to SVC.^[22] Several investigators selected markers within/near IL genes such IL1, IL6, IL4, IL10, IL12B, IL18, IL19/IL20, IL22 or IL10RA and their natural receptors, as candidate genes in exploring HCV infection risk.^[23–31] Overall, these studies lack the consistence observed for the HLA region; the findings have not been systematically confirmed^{[22,24,26,32,33]} and remain controversial. Most of these studies need to be considered preliminary and require corroboration in larger series. IL10 is located at 1q32 chromosomal region within a cluster of paralog genes comprising IL10, IL19, IL20 and IL24 cytokines. The protein encoded by this gene is a cytokine produced primarily by monocytes, and to a lesser extent, by lymphocytes. This cytokine has pleiotropic effects in immunoregulation and inflammation. It down-regulates the expression of T helper 1 (Th1) cytokines, MHC class II antigens and co-stimulatory molecules on macrophages. It also enhances B cell survival, proliferation and antibody production. High IL10 levels have been related to disease progression^[34] and IL10 polymorphisms have been associated with SVC in at least four independent studies.^{[23,25,28,29]}

Some genetic signals observed in loci such as TGFβ1,^[35] CTLA4,^[36] interferon regulatory factor-1 (IRF-1),^[37,38] C–C motif chemokine receptor gene cluster,^[39,40] LTA (a gene of the HLA region),^[41] STAT1 or interferon alpha2 (INFA2)^[42] and interferon gamma^[43] require further validation. Lastly, genetic elements not directly related to the immune system, most of them HCV-interacting proteins, are involved in different stages of HCV lifecycle. The role of claudin 1 coreceptor, involved in late-stage HCV binding to the cell,^[44] or polymorphisms in the low-density lipoprotein receptor (LDL-R) gene involved in viral endocytosis^[45,46] together with apolipoproteins (apoE and apoB) are used by HCV as blood vehicles that facilitate interaction with the LDL receptor during HCV endocytosis.^[47,48] ApoE can also be recruited by HCV machinery during late stages of lifecycle for viral assembly.^[49] APOE¢4 alleles might protect against severe liver disease^[50] but APOE¢3 allele has been associated with HCV infection persistence.^[51] In addition, variability in the promoter region of the APOB gene might also modify HCV susceptibility.^[49] Hence, the apolipoprotein variability hypothesis for HCV infection seems attractive, and further research is warranted. Factors influencing the interaction between host and the virus, such as the paraoxonase-1 (PON1)-192 polymorphism^[52] could contribute, together with other polymorphisms, to the variations in the host response to HCV infection.

Genome-wide Association Studies in Susceptibility Analysis

In addition to information obtained using hypothesis-driven studies (the candidate gene approach), we now have information from early GWAS analyses conducted to identify the mechanisms underlying spontaneous HCV clearance. Overall, these hypothesis-free investigations using massive, parallel, genotypic research technologies (DNA arrays) combined with the emerging independent studies that reproduce these findings have provided incontrovertible evidence that genomic variation near the IL28B locus is directly related to SVC. IL28B encodes a cytokine distantly related to type I IFNs and the IL10 family. Together with IL28A and IL29, there are three closely related cytokine genes that form a cytokine gene cluster on a chromosomal region mapped to 19q13. Expression of the cytokines encoded by the three genes can be induced by viral infection. All three cytokines have been shown to interact with a heterodimeric class II cytokine receptor that consists of interleukin 10-receptor beta and interleukin 28-receptor alpha. Both receptors are now strong candidates for further genetic analysis. In the initial study, Ge et al.^[53] found a higher prevalence of the CC genotype in healthy individuals compared with those with chronic hepatitis C (CHC) (73 vs 63%; P<2.5 × 10⁻⁶). However, these differences have not been confirmed in subsequent studies. Thomas et al.^[54] evaluated a cohort of 388 patients who spontaneously resolved the infection and compared them with 620 patients with CHC. Genotype CC from the rs12979860 in the IL28B gene was found in 58.5% (227/388) of patients with spontaneous clearance and in 32.6% (202/620) of patients with CHC (P=3 × 10⁻¹³). These results have been confirmed in two further studies. Montes-Cano et al.^[55] confirmed that the prevalence of genotype CC in patients with SVC was two-fold that of chronic carriers. Rauch and colleagues conducted a GWAS and identified a genetic signal in chromosome 19 that was strongly related to spontaneous clearance, irrespective of HIV co-infection or route of infection. Moreover, gender remained an independent variable associated with spontaneous clearance (OR: 1.7; 13–2.4).^[56] Indeed, the distribution of IL28B rs12979860 genotype CC was similar in males and females (72.5 vs72.4%; P=NS) with spontaneous clearance. Lastly, spontaneous clearance rate was lower in males and in Afro-Americans (AAs). In AA, the prevalence of the polymorphism was higher in patients with SVC [genotype CC: 33% (32/97) vs. 13.5% (26/193) than in patients with CHC; P=1 × 10⁻⁴].

In summary, as hypothesized previously, genetic factors play a key role in clearing the virus post-infection. HLA class II and some genetic signals located in the 19q13 region, including IL28B, KIR2DL3, TGFβ1, LDLR and APOE, are the strongest predictors of spontaneous clearance (Table 1) Table 1b, 1c.

Genetic Factors Related to Fibrosis Progression

Fibrosis progression is the main prognosis determinant of liver disease outcome in CHC.^[57] The natural history of the infection clearly shows a subgroup of patients chronically infected with HCV (a range from 5 to 20% in several cohort studies^[58]) who gradually could progress to cirrhosis and to end-stage liver disease. Patients may be classified according to Metavir score from F0 to F4. In genetic studies, the fibrosis phenotype could be analysed in two different ways: (a) patients who reached advanced fibrosis (F3–F4 vs F0–F2); (b) fibrosis progression rate, i.e. dividing fibrosis detected in liver biopsy (0–4) by duration of infection (in years). Variables associated with fibrosis progression include: (a) age at infection; (b) alcohol intake (>50 g/day); (c) male gender; (d) hepatitis B co-infection; (e) immunodeficiency because of HIV or the use of immunosuppressant drugs such of those used after liver transplantation; (f) excess weight; (g) liver steatosis; (h) presence of metabolic syndrome and/or type II diabetes; (i) iron overload.^[59] Host genetic factors might have a relevant influence on the natural history of CHC. Many studies have implicated several SNPs (single nucleotide variations at specific positions of the genome detected in more than 1% of population) in order to analyze their possible impact on fibrosis progression, and the risk of hepatocellular carcinoma.^[60]

Candidate Genes Implicated in the Immune and Inflammatory Response: Human Leucocyte Antigen and Interleukins

Human leucocyte antigen class II haplotypes, mainly of DRB1, were associated with persistently normal alanine transaminase (ALT) and mild fibrosis^[61,62] in a cohort of 83 patients with normal ALT levels over a 6-month period and 233 patients with elevated ALT. HLADRB1*11 was overrepresented in those with normal ALT levels (43 vs 24%, OR: 2.36) and mild fibrosis.^[63] Moreover, DRB1*11 allele was associated with a lower progression rate (1.58 vs 2.14) and a lower probability of developing cirrhosis.^[64] However, other studies did not find this association between HLA class and fibrosis progression.^[65,66] Association studies of fibrosis progression with polymorphisms in chemokine receptor 5 (CCR-5), monocyte chemotactic protein 2 (MCP-2) and monocyte chemotactic protein-1 (MCP-1) are conflicting in their findings. Hellier et al.^[67] included 337 patients in their study and found that the Δ–32 deletion was associated with more advanced fibrosis (OR=1.97; P=0.015), but with reduced portal inflammation. These results have not been confirmed in other studies but, instead, have been contradicted.^[68–70] Despite an initial association observed between MCP-2 and MCP-1^[71] with fibrosis, subsequent studies have not confirmed this association.^[72,73] Kato and colleagues^[74] studied nine SNPs of the interferon regulatory factor-7 (IRF-7) gene (four of these SNPs in the promoter region) in 406 patients (178 with cirrhosis). Two non-synonymous SNPs at positions 1047 and 2157 (A-to-G in both cases) resulting in amino acid changes (Lys/Glu and Gln/Arg respectively) were reported. The polymorphisms 1047AG and 2157AG were in complete LD, and they were more frequently seen in cirrhotic patients (5.6%) than in non-cirrhotic individuals (1.7%) (OR: 3.27; P=0.03). However, there was no association between SNPs in the promoter region and the presence of cirrhosis. In multivariate analysis, 1047AG and 2157AG were independently associated with cirrhosis (AA vs AG-adjusted OR: 2.5; 95% CI: 1.2–5.6; P=0.02). IRF-7 has been found to affect immune responses mainly by regulating the transcription of IFN-stimulated genes.^[75] Additional possible mechanisms for the effect of IRF-7 gene polymorphisms on the progression of liver fibrosis include the IRF-7-induced activation of IFN-β and regulated on activation normal T cell expressed and secreted (RANTES). RANTES serves as a key ligand for CCR5 and plays a significant role in attracting T cells to the portal area of the liver infected with HCV. The activation of RANTES has been suggested to be involved in the progression of CHC to advanced forms of liver disease.^[76,77] IL10 is known to influence the Th1/Th2 cytokine profile, affecting both the innate and adaptive immune responses to infection. HCV has been shown to induce the activation of IL10 secretion, and increased IL10 production has been observed to correlate with persistent HCV infection, higher inflammation grade and an increased risk of liver cancer. Two receptor chains, IL10RA and IL10RB, are known to mediate the functions of IL10. Although SNP in the minor allele in G330R IL10R1^[78] and the homozygosity for two IL10 haplotypes:^[79,80] −819 (Cto-A); and −1082 (AA genotype, ATA/ATA and ACC/ACC) have been reported to be associated with faster fibrosis rates, contradictory findings have been observed in different studies evaluating the significance of this last-mentioned polymorphism. Hennig et al.^[30] examined 631 HCV patients and found a variation in IL10RA, IL10RA-rs9610 (3'-UTR), which appeared to be correlated with reduced inflammation, individuals carrying an A allele being less likely to present with severe inflammation (OR=0.29; 95% CI: 0.10–0.83; P<0.05). IL18, also called IFN-c–inducing factor, is an obligatory cytokine for IFN-c production, and plays a key role in the induction of Th1 responses and viral clearance as well as in the development of liver fibrosis. Single-nucleotide promoter polymorphisms influence the transcription of IL18 mRNA. Pro-IL18 is a biologically inactive precursor that is produced by monocytes, macrophages and immature dendritic cells during an acute immune response. It is activated intracellularly by caspase-1 to induce IFN-c, iNOS (inducible nitric oxide synthetase), TNF-α secretion, as well as induction of other inflammatory cytokines such as IL6, IL8, IL2, MCP-1, MIP-a and MIP-b. Increased IL18 production is neutralized by IL18BP in CHC infection, and this neutralization is crucial for the regulation of inflammation and fibrosis development. Manohar et al.^[81] have investigated the association between the −607 polymorphism and severity of HCV infection. They evaluated 204 patients with CHC and 350 matched healthy controls. The −607 A/A allele was more common in patients with mild disease than in patients with severe diseases (38.6% vs 21%, OR=0.424; P=0.05). IL18 promoter −607 A/A allele is a potential protective marker in patients with CHC. These results have been confirmed by another study.^[82] IL12 is a cytokine that induces production of the IFNγ. Suneetha et al.^[83] showed that homozygosity for the minor allele of this SNP, 1188C/C, was more common in patients who had mild fibrosis compared with those with severe fibrosis (23.7 vs 6.25%; P=0.004). Several studies have shown that TNF may play a role in the pathogenesis of CHC by influencing fibrosis progression rate. Dai et al.^[84] investigated the biallelic polymorphism G vs A in the promoter region at positions −308 (TNF308.2) and −238 (TNF238.2). In 250 biopsy-proven CHC individuals, the TNF 308.2 allele copy numbers were significantly associated with more severe fibrosis stage (F3–F4; P=0.006) and higher mean fibrosis score (P=0.007). Logistic regression analysis showed that a higher fibrosis score was independently related to the TNF308.2 allele (OR: 1.38). However, conflicting results have been reported on this association.^[85,86] ApoE binds to some cellular receptors including proteoglycans, heparan sulphate and LDL-R. The HCV competes with the apoE in the process of entry into the cell via the LDL-R. Specifically, apoE4 is the protein subtype with more affinity for these receptors while the apoE-2 has the lowest affinity. Patients carrying ¢4 allele seem to be protected against cirrhosis (4.3 vs 19.1% in ¢2/¢3 allele carriers). In a cohort of 111 patients, the ¢4 allele was associated with a lower risk of cirrhosis when evaluated in the multivariate analysis that took into account confounding factors such as gender, alcohol intake, time of evolution of the infection and the age at biopsy^[87] However, APOB SNPs did not influence liver fibrosis rate.^[47] SNPs at positions 1874 (T-to-A) of the IFN-γ gene has also been described as accelerating the rate of fibrosis progression in HCV patients.^[88] The enzyme 2'-5'-oligoadenylate synthetase 1 (OAS-1), an important component of the innate immune system, has an antiviral function.^[89] Li et al.^[90] reported the association between six SNPs of OAS-1 and fibrosis in 409 patients with HCV. Patients with rs3741981 genotypes A/A, A/G and G/G of an SNP of OAS-1 at the exon 3 were at a gradient increased risk of fibrosis progression and suffering from cirrhosis (P=0.001). Multivariate logistic regression analysis indicated that genotype G/G was an independent factor associated with cirrhosis (OR: 3.11; P=0.013). Mannan-binding lectin (MBL), encoded by the MBL2 gene, can have an important role as an opsonin and complement-activating molecule with an important function in the initiation, regulation and amplification of immune response. A small number of studies have examined the relationship between MBL polymorphisms and HCV infection. These studies differ with respect to the cohorts used, categorization of subjects and the MBL gene mutations investigated. Brown et al.^[91] demonstrated an association of higher MBL/MASP-1 complex activity (related to polymorphisms in the promoter and structural regions of MBL gene) with severity of fibrosis in HCV. In 102 Euro-Brazilian patients,^[92] MBL2 polymorphism was associated with moderate and severe fibrosis in CHC, after controlling for gender and age. Six common SNPs, three in the promoter (H/L, X/Y and P/Q) and three in exon 1 (A, the wild-type, and B, C or D also known as O) were evaluated using real-time polymerase chain reaction (RT-PCR) with fluorescent hybridization probes. The frequency of the YA/YO genotype was significantly higher in H patients vs the controls (P=0.022). Genotypes associated with low levels of MBL (XA/XA, XA/YO and YO/YO) were decreased significantly in the patients with severe fibrosis (stage F4) compared with patients with moderate fibrosis (stage F2) (P=0.04) and to the control group (P=0.011). Genes involved in the transduction of myxovirus (MxA) and protein kinase R (PKR) together with pro-inflammatory cytokines involved in IFN resistance such as IL10, TNF, IL6, GH and IL1 have been selected for candidate gene analyses. Yee and colleagues investigated the association between myxovirus resistance-1 (Mx1), PKR, liver fibrosis in 374 treatment-naive patients with genotype-1 chronic HCV infection (194 Caucasian Americans CAs and 180 Aas), using a genetic haplotype approach. He reported independent association between Mx1-CAGT and PKR-TGATT and less severe hepatic fibrosis even after control for the confounding factors such as race and gender. However, the associations were not statistically significant in a second, independent validation cohort.^[93]

Candidate Genes Implicated in Iron Metabolism as Fibrogenic Factor

Iron overload seems to induce a deleterious effect on fibrosis progression rate. However, the relationship between the presence of HFE gene mutations and disease progression remains controversial. Some authors have reported a strong association between mutations and fibrosis progression^[94] while others have not observed these relationships.^[95–97] Thorburn et al.^[98] in a large cohort did not detect association, whereas Erhardt et al.^[99] did, and highlighted that their systematic study demonstrated that the association between HFE gene mutations and progression was independent of other confounding variables. Tung et al.^[100] studied 316 CHC patients and highlighted that heterozygous mutations in both exon 2 and exon 4 were associated with increased histological damage, and a faster fibrosis progression rate. No associations between histological progression of liver disease and TfR1 SNPs^[101–103] have been reported. Further, Nramp1 protein, now termed solute carrier family 11 member 1 (SLC11A1) protein is located in the late endosomal compartment of resting macrophages, and is recruited to the phagosome by phagocytosis and seems to be an intracellular transporter of iron, while playing an important role in immune response against intracellular microorganisms such as HCV. Several mutations resulting in polymorphic mRNA expression have been identified in the SLC11A1 gene (2q35). Four alleles have been found in different populations with the absence of allele 3 exerting a protective effect on progression to cirrhosis in patients with HCV. In a Spanish cohort that included 242 patients with biopsy-proven CHC and 194 healthy control subjects, allele 3 carriers showed faster fibrosis progression rate of 0.16 ± 0.20 vs 0.09 ± 0.08 units of fibrosis/year. Hence, the 2/2 genotype of the promoter region of the SLC11A1 gene was found to be associated with mild portal inflammation and a lack of advanced fibrosis (OR: 8.85; P=0.002). Indeed, the interaction between allele 3 of SLC11A1 and the -238 A/G mutations in the promoter region of TNF gene appears to promote accelerated progression of fibrosis (OR: 2.53; P=0.039).^[104]

Candidate Genes Implicated in Hepatic Stellate Cell Activation

TGFβ1 plays a significant role in hepatic stellate cell activation, and increased levels of this chemokine have been related to a faster rate of fibrosis progression.^[105] Several polymorphisms have been described: Arg/Pro mutation at codon 25 (G/C carriers) induces a rapid progression to cirrhosis with a progression rate of 0.23 vs 0.008 of the Arg/Arg group (non-mutated TGFβ1). These results proceeded from studies with small series of subjects but have been confirmed in further cohorts.^[106–109] Thus, SNPs from these 2 genes (TGFβ1 and AT) are confirmed as being implicated in fibrosis progression. Several factors such as hyperhomocysteinaemia and C protein deficiency as well as increased factor VIII:C have been associated with fibrosis progression.^[110] Factor V Leiden mutation A560G has been associated with an increased risk of cirrhosis and faster fibrosis progression (0.37 vs 0.18 units of fibrosis/year).^[111,112] Inhibition of thrombin receptor protease-activated receptor 1 polymorphism, 1426 (C/T instead of T/T);^[113] or myeloperoxidase gene −463A have been shown to be associated with greater fibrosis.^[114,115] With the haplotype approach, Mx1-CAGT and PKR-TGATT haplotypes of antiviral genes were independently associated with mild liver fibrosis, following adjustment for potential confounders (for Mx1-CAGT haplotype: OR: 0.33; P=0.0027; for PKR-TGATT haplotype: OR: 0.56; P=0.0405). These findings were validated using an independent cohort in which a protective trend for the PKR-TGATT and Mx1-CAGT haplotypes was confirmed, albeit the association with the latter haplotype was not statistically significant.

Genome-wide Scan and Fibrosis Progression

A genome-wide scan including 24 823 candidate SNPs from 12 248 covering genes in 433 biopsy-proven CHC individuals identified 100 SNPs associated with an increased risk of advanced fibrosis.^[116] In 483 patients from the validation cohort, only two out of 100 were found to be associated with advanced fibrosis. A missense SNP in the DEAD (Asp–Glu–Ala–Asp) box polypeptide 5 gene causing an amino acid replacement at position 480 (S480A) in exon 13 was associated with an increased risk of advanced fibrosis (OR: 1.8 and 2.3 in the 2 cohorts), while a missense SNP in the carnitine palmitoyltransferase 1A gene causing amino acid change at position 275 (A275T) in exon 8 was associated with a decreased risk for advanced fibrosis (OR: 0.3 and 0.6 in the 2 cohorts). A cirrhosis risk score (CRS) based on genetic markers identified from two Caucasian cohorts was derived from 361 SNPs showing associations with fibrosis. Seven SNPs (one SNP in the antizyme-inhibitor-1 gene, one SNP in the Toll-like receptor-4 gene and 5 SNPs in five other genes of unclear function) showed the highest predictability for cirrhosis.^[117] CRS offered a better prediction of cirrhosis compared with clinical factors (age, gender and alcohol abuse). Two CRS cut-off values were eventually suggested to identify the majority of patients at low risk (<50) and those at high risk (>70) of developing cirrhosis. Genetic CRS has been recently confirmed by Li et al.^[118] in 420 Caucasian individuals and by Marcolongo et al.^[119] in 271 patients with mild fibrosis followed-up over 60 months without therapy. The best prediction accuracy of CRS was in males with no fibrosis at baseline.

Genetic Variations and Sustained Response to Peginterferon+ribavirin Treatment

Sustained virological response rate variability following a course of Peg-IFN/RBV treatment is extremely high. Genotype, viral load, fibrosis and metabolic disturbances including obesity, insulin resistance and steatosis were the factors most influential in SVR.^[120] Several SNPs from candidate genes have been associated with achieving SVR in patients receiving Peg-IFN/RBV treatment. Regulatory genes of IFN antiviral activity, immune-response genes and genes implicated in obesity and in insulin resistance have been analysed. The mechanism of action of IFN has been characterized, and the key points identified are: (a) interaction with IFN alpha receptor; (b) Janus-kinase and tyrosin-kinase activity; (c) STATs phosphorylation; (d) synthesis of antiviral proteins such as 2'–5' OAS, MxA protein induced by IFN. Intracellular MxA, which works like GTPase to achieve its antiviral effect, seems to be the most specific marker of antiviral activity of IFN. In patients receiving induction doses of IFN, MxA levels increased in parallel with antiviral activity.^[121] SNP −88T in the MxA gene was found to be associated with lower MxA protein activity. In patients with a low viral load, SVR was statistically significantly higher (62%) in −88T patients than in patients bearing the −88A allele (32%).^[122] The 2'–5' OAS enzyme plays a major role in the clearance of the virus. However, some studies that had included analysis of the GG genotype (in the 3'UTR region) do not predict SVR.^[89] Lastly, a tandem repeat of three nucleotides in the PKR gene classified as 'large' when containing >9 repeats has been found to be associated with SVR. Large/large polymorphism was more often seen in patients achieving SVR than in non-responders (89.4 vs 71.8%; P=0.017).^[13] ApoE has been implicated in the mechanism of entry of the HCV into the cell via the LDL-R. In a cohort of 506 patients treated with Peg-IFN/RBV, the ¢4 allele was found to be associated with poorer response in patients with genotype 1 (30 vs 42%; P<0.05).^[123] Several polymorphisms from proinflammatory cytokines have been included as candidate genes in the prediction of SVR. The biallelic polymorphism in TNF (−238 and −308) seems not to be associated with SVR.^[124] TGFβ1 and interleucin-10 polymorphisms have been strongly related to achieving SVR. Genotype −29 C/C in TGFβ1 promotes resistance to Peg-IFN/RBV treatment.^[125] Further, genotypes −592 A/A and −819 T/T in the IL10 gene have been found to be linked to higher SVR.^[126] Lastly, in a multivariate analysis of 105 patients treated with IFN/RBV, HLA class I B44 was seen to be independently associated with improved SVR to combined IFN/RBV, together with viral non-1 genotype. However, no association between this allele and SVR was detected in patients receiving IFN alone.^[127] In spite of these well-selected candidate genes, and some associations being confirmed in multivariate analysis, the majority of them showed minor impact on clinical practice, and they have not been included in the daily management of patients with CHC.

Several pharmacogenetic studies using GWAS for HCV treatment response assessment have demonstrated relationships between several polymorphisms in the 19q13 region and SVR (Table 2). Ge and colleagues conducted a GWAS analysis in 1137 patients of a cohort from the IDEAL study; a trial comparing Peg-IFN α-2b in two different doses (1.0 μg/kg/week vs. 1.5 μg/kg/week) versus standard doses of Peg-IFN α-2a. Using the Illumina Human 610® quad bead chip, the authors demonstrated that the probability of achieving SVR in patients bearing CC in the position rs12979860 in 19q13 region was double that of those with CT/TT (OR: 2; 95% CI: 1.8–2.3; P=1.37 × 10⁻²⁸). Moreover, the distributions of this CC genotype in several World populations were strongly related to SVR whether in Asians, Europeans, Hispanic or AAs. Tanaka et al.^[128] conducted a GWAS analysis in 154 Japanese patients; 82 non-responders and 72 with SVR using Affimetrix SNP 6.0® genome wide SNP typing array testing 621 220 SNPs. Several genetic signals in the 19q13 region were observed to be strongly related to SVR (rs12980275; P=1.93 × 10⁻¹³ and rs8099917; P=3.11 × 10⁻¹⁵). Sequencing a 40 kb region in the 19q13 region indicated that 7 SNPs were strongly related to each other, suggesting that the association with SVR was primarily driven by one or other of these SNPs. Further, using quantitative RT-PCR, IL28B mRNA was found to be higher in patients who were homozygous carriers of the major allele. Lastly, multivariate analysis indicated that rs8099917 (G allele) and female gender were independently associated with SVR while fibrosis, markers of liver dysfunction (such as platelets) or viral load were excluded from the final multivariate model. Suppiah et al.^[129] conducted a GWAS of SVR to Peg-IFN/RBV in 293 Australian patients with genotype 1, and a validation cohort of 555 individuals. An association between rs8099917 in the IL28B gene and SVR was observed (OR: 1.98, 95% CI: 1.57–2.52; P<0.05) confirming the previous data from Ge and colleagues. In a recent GWAS analysis, all these markers in the 19q13 region were found to be associated with SVR but, after multivariate analysis, rs12979860 was found to be independently associated with the chance of achieving a cure, and as such, supporting a major role for this genetic signal.^[130] These results have since been confirmed in different series such as those of McCarthy et al.,^[131] Del Campo et al.,^[132] Montes-Cano et al.^[55] and Rauch et al..^[56] Further, this polymorphism has also been strongly associated with the possibility of achieving SVR in patients infected by genotype 1, without rapid virological response (RVR) (clearance of the virus after 4 weeks of treatment).^[133] Conversely, in patients with CHC non-1 genotype, IL28B polymorphism rs8099917 G was not associated with higher SVR. In 230 patients with genotype 2 or 3 receiving Peg-IFN/RBV, SVR was 79.5% in patients bearing the G allele vs 86.4% in patients with the T allele (OR: 1.62; 95% CI: 0.8–3.3; P=NS).^[58] Recently, Mangia et al.^[134] confirmed the usefulness of genotype CC in predicting SVR in patients with genotype 2/3 without RVR, but not in the overall cohort (Table 3).

Further, favourable polymorphism rs12979860 was more often seen in genotype 2, 3 than genotype 1 (Fig. 1) suggesting that IL28B polymorphism not only strongly influences SVR but also appears to explain much of the difference in response observed between population groups representing different viral genotypes and host ethnicity.^[57] A meta-analysis including all these studies was conducted (Fig. 2) and all studies confirmed the association between genotype CC rs12987960 and SVR (OR: 4.5; 95% CI: 2.8–7.3). In a multivariate analysis of HCV-4 patients, baseline viral load, fibrosis and the IL28 T allele (OR: 0.124, 95% CI: 0.030–0.505) were significantly associated with SVR.^[106] The strongest predictor for the final outcome was RVR (OR: 26.00; 95% CI: 7.148–94.545, P<0.0001). If RVR was included in the multivariate model, only the RVR and the fibrosis score remained significant. Thus, determination of IL28 polymorphism may not be useful to select patients with HCV-4 for abbreviated treatment schedules.^[135] IFN-λ is transduced from IL28B gene (19q13). It binds to the heterodimer receptor complex composed of 2 subunits IFN-λ-R1 and IL10-R2. After receptor binding, IFN-λ has been observed to promote the JAK-STAT antiviral pathway, inducing phosphorylation of Janus-kinase1 and tyrosine-kinase2, promoting signal transducer and activating transcription (STAT) phosphorylation. After coupling with IFN, regulatory factor 9 translocates to the nucleus and binds the IFN-stimulated response element in DNA to initiate gene t

ranscription, mainly IFN-stimulated genes including 5'2'OAS, protein-tyrosine-kinase, IL8 and IFN-regulated factor-7. Thus, IFN-l, seems to be able to: (a) inhibit HCV replication; (b) down-regulate HLA-I presentation; (c) inhibit the entry of HCV particles into the ribosome; (d) have better haematological tolerance than IFN alpha, mainly because of reduced expression of IFN-λ-R1 receptor in blood cells. Nevertheless, the specific genetic variant involved remains to be determined, together with the amino acid change that could promote the protein. Indeed, antiviral activity of IFN-λ3 varies depending on the final amino acid change: Val97 to Ala increases 68-fold the antiviral activity, while Arg51 to Ala does not modify it.^[136]

Figure 1.

Genotype CC (rs12979860) distribution in spontaneous viral clearance (n=69), healthy individuals (n=1169) and chronic hepatitis C (n=524) in Spain.

Figure 2.

Estimated impact of rs12979860 genotype on the possibility of achieving sustained virological response in patients infected by genotype 1. Note: Half of the responders are non-CC genotype.
.

Overall, these hypothesis-free investigations using massive, and parallel, genotypic research technologies such as DNA arrays, together with independently reproduced studies, have provided incontrovertible evidence that genomic variation in or around the IL28B locus is directly related to SVR induced by Peg-IFN/RBV therapy. The genetic variant (or variants) needs to be described, as are the functional analyses to demonstrate the impact of these changes on the host's ability to clear viral infection. Further, the role of the genetic alteration in patients infected by non-1 genotypes should be demonstrated; IL28 polymorphism may not be useful in selecting patients with HCV-4 for abbreviated treatment schedules. However, these data need further confirmation before final conclusions can be formulated. Lastly, from a clinical point of view, approximately a third of patients bearing the CC genotype (rs12979860) did not achieve SVR, while on the other hand, nearly a half of CT heterozygous and a third of TT homozygous individuals could achieve SVR when treated with Peg-IFN/RBV. Thus, genetic factors that could modulate (positively or negatively) the effect of this polymorphism on SVR warrant further exploration. Perhaps other genetic markers could explain this gap between IL28B genotype and SVR^[137] (Fig. 3).

Click Figure To Enlarge

Figure 3.

Meta-analysis showing a strong association between sustained virological response and genotype CC (rs 12987960).
/

In conclusion, the lessons from the review of these studies are: (a) there are innate host characteristics that model HCV lifecycle and infection resolution; (b) the investigation of SVR and SVC are fully complementary. This means that host genetic factors might behave similarly by simultaneously affecting both phenotypes; (c) together with HLA region studies and meta-analyses related to them, GWAS have provided overwhelming evidence indicating that the host immunological hypothesis for virus clearance is plausible; (d) the isolation of this unanticipated factor (IL28B) will provide new research opportunities and will have a considerable clinical impact on HCV diagnosis, prognosis and therapy in these patients; (e) based on genetic studies, spontaneous clearance or fibrosis progression can be considered as complex phenotypes. This assumption implies that many other genetic and non-genetic factors need to be identified, using candidate gene or hypothesis-free approaches. To achieve these goals, genetic markers need to be studied in large cohorts of patients, keeping in mind their interaction with environmental and viral factors, which could affect the natural history of CHC. We feel that genetic studies are opening up a new era in HCV investigation. However, despite recent successes, there is still a considerable gap between genetic discoveries in the laboratory and application of the findings to innovative clinical practice; fortunately, it is a gap that is continuing to close.

• References
• http://www.medscape.com/viewarticle/740571_2

IL28B CC or CT genotype have better liver graft survival in Hepatitis C

By Nancy Lapid

PHILADELPHIA (Reuters Health) May 03 - Researchers are a step closer to knowing which hepatitis C patients are more likely to lose their grafts after liver transplantation.

According to study results announced yesterday at the American Transplant Congress in Philadelphia, hepatitis C patients with the IL28B CC or CT genotype have better graft survival and longer times to histological recurrence than recipients with the TT genotype.

Hepatitis C viremia inevitably recurs after liver transplantation, leading to high rates of cirrhosis and graft loss. The new findings could mean that directing lower-risk organs (e.g., from younger donors, or with shorter cold ischemia times) to higher-risk recipients might improve their outcomes.

"This is clearly something that could have clinical implications," senior investigator Dr. Barbara Murphy from Mount Sinai Medical Center in New York City told Reuters Health. "There's already a lab-based assay available, so we could genotype the recipients. Certain labs have this up and going."

But Dr. Murphy won't say transplant programs should act now on these results. Her study, while large, was retrospective. "If you're going to change organ allocation -- if you're going to give one group preference for better organs -- you'd better have data" from randomized trials, she said.

Studies in hepatitis C patients who still have their native liver had already pointed to an impact from the IL28B gene, Dr. Murphy said. Individuals with the favorable polymorphism are more likely to have spontaneous clearance or a sustained virologic response to interferon-based therapy.
In a plenary session talk yesterday, her colleague Dr. Sridhar R. Allam reported on a study of 620 adult liver recipients for whom DNA samples were available for genotyping of IL28B (rs12979860); the cohort included 327 hepatitis C virus HCV-positive patients.

The research team also had genotype data for a subgroup of 377 consecutive donor DNA samples, and IL28B gene expression data from RNA isolated from pre-implantation liver biopsies of 33 donors.
Dr. Allam reported significantly better five-year graft survival with the IL28B CC or CT genotype vs. the TT genotype (61.8% vs. 47.9%, p=0.02) in patients with HCV infection. In the non-HCV control group, however, there was no difference in graft survival based on IL28B genotype.
Also, he said, recipients with C allele had delayed mean time to histological HCV recurrence after LT (25 vs. 15 months, p=0.02).

There was no association of donor IL28B genotype with graft survival, and no effect of IL28B genotype on IL28 RNA expression.

IL28 is known to affect innate immunity, but it's not clear why it impacts graft survival, Dr. Allam said.
When researchers do design randomized trials, among the most important things they'll want to see is whether any interventions -- such as shifting better-quality livers to patients at higher risk for graft loss -- will actually change outcomes, Dr. Murphy said.

Also, it will likely be important to consider IL28B genotype in trials of new protease inhibitors for HCV. "You would think the polymorphism would point to outcome," Dr. Murphy said. "They'll need to look for this in trial populations, to make sure it's not skewing the data."

 

Hepatitis C cases on rise among Massachusetts youth

05 May 2011 20:48

Source: reuters // Reuters

* Injected drug use driving spike among those 15-24
* Heroin use common among those newly infected

CHICAGO, May 5 (Reuters) - Hepatitis C infections are rising quickly among white youth in Massachusetts, fueled by increases in the use of heroin and other injection drugs, local and federal health researchers said on Thursday.

Cases of the infection -- a leading cause of liver damage and cancer -- have been dropping across the general population, but they started rising in youth aged 15 to 24 between 2002 and 2006, a trend that continued through 2009, a team from the Massachusetts Department of Public Health reported.
"Of cases with available risk data, injection drug use was the most common risk factor for HCV transmission," the team wrote in the U.S. Centers for Disease Control and Prevention&apos;s weekly report on death and disease.

"The increase in case reports appears to represent an epidemic of HCV infection related to IDU (injected drug use) among new populations of adolescents and young adults in Massachusetts," they wrote.
The CDC said in an editorial is had been documenting cases of Hepatitis C infection for decades, but it called the recent epidemic among adolescents and young adults and its apparent link to IV drug use "a disturbing trend."

"Law enforcement data suggest this trend might be occurring in other states," the CDC said, citing data showing increases in first-time heroin use, which jumped to 180,000 in 2009 from 100,000 in 2002.
Law enforcement reports from officials in the Great Lakes, Mid-Atlantic, New England, New York/New Jersey, Southeast, and West Central regions also suggests that heroin use is increasing, particularly among younger users.

Hepatitis C, an infection caused by a virus that attacks the liver, is considered one of the most serious of the hepatitis viruses. It is commonly passed through contaminated blood -- often through needles shared during illegal drug use.

The latest cases were reported from across Massachusetts, mostly among non-Hispanic whites, and were split evenly between males and females.

Of 1,196 cases in which doctors had a history of potential risk factors, 72 percent were in people who reported current or past injection drug use.

Among the 719 people who said they injected drugs in the preceding 12 months, 85 percent said they had used heroin, 29 percent had used cocaine, 1 percent had used methamphetamine and 4 percent had used other drugs.

They said the study suggested the need for better monitoring of Hepatitis C infection and better prevention efforts targeting adolescents and young adults, they said.
According to the CDC, 3.2 million Americans are infected. Most people who are newly infected have no symptoms.

(Reporting by Julie Steenhuysen in Chicago; Editing by Peter Cooney)

FDA Issues First New Rules Under Food Safety Modernization Act

PR Newswire

SILVER SPRING, Md., May 4, 2011

Rules to prevent potentially unsafe food from reaching consumers

SILVER SPRING, Md., May 4, 2011 /PRNewswire-USNewswire/ -- The U.S. Food and Drug Administration today announced two new regulations that will help ensure the safety and security of foods in the United States. The rules are the first to be issued by the FDA under the new authorities granted the agency by the FDA Food Safety Modernization Act (FSMA), signed into law by President Obama in January. Both rules will take effect July 3, 2011.  

The first rule strengthens FDA's ability to prevent potentially unsafe food from entering commerce.  It allows the FDA to administratively detain food the agency believes has been produced under insanitary or unsafe conditions.  Previously, the FDA's ability to detain food products applied only when the agency had credible evidence that a food product presented was contaminated or mislabeled in a way that presented a threat of serious adverse health consequences or death to humans or animals.

Beginning in July, the FDA will be able to detain food products that it has reason to believe are adulterated or misbranded for up to 30 days, if needed, to ensure they are kept out of the marketplace. The products will be kept out of the marketplace while the agency determines whether an enforcement action such as seizure or federal injunction against distribution of the product in commerce is necessary.

Before this new rule, the FDA would often work with state agencies to embargo a food product under the state's legal authority until federal enforcement action could be initiated in federal court.  In keeping with other provisions in the FSMA, FDA will continue to work with state agencies on food safety and build stronger ties with those agencies.

"This authority strengthens significantly the FDA's ability to keep potentially harmful food from reaching U.S. consumers," said FDA Deputy Commissioner for Foods Mike Taylor.  "It is a prime example of how the new food safety law allows FDA to build prevention into our food safety system."

The second rule requires anyone importing food into the United States to inform the FDA if any country has refused entry to the same product, including food for animals.

This new requirement will provide the agency with more information about foods that are being imported, which improves the FDA's ability to target foods that may pose a significant risk to public health.

This new reporting requirement will be administered through the FDA's prior notice system for incoming shipments of imported food established under the Public Health Security and Bioterrorism Preparedness and Response Act of 2002.

With prior notice, in the event of a credible threat for a specific product or a specific manufacturer or processor, the FDA is able to mobilize and assist in the detention and removal of products that may pose a serious health threat to humans or animals.

"The new information on imports can help the FDA make better informed decisions in managing the potential risks of imported food entering the United States," Taylor said.  "These rules will be followed later this year and next year by a series of proposed rules for both domestic and imported food that will help the FDA continue building the new food safety system called for by Congress."  

The issuance of these rules is the latest accomplishment of FDA in implementing the new food safety law.  In April, the FDA launched a consumer-friendly web search engine for recall information and issued the first annual report to Congress describing FDA's activities in protecting the U.S. food supply. FDA also released a guidance document to the seafood industry on ways to reduce or eliminate food safety hazards.  

In addition, since the law was signed, the FDA has held two large public meetings with industry and consumer groups on the import and preventive control provisions of the law, and reached out extensively to partners in other federal, state, and foreign governments.

For more information:

• FDA Web Page:  Food Safety Modernization Act (http://www.fda.gov/Food/FoodSafety/FSMA/default.htm)
• Federal Register Notice for Interim Final Rule on Criteria Used to Order Administrative Detention of Food for Human or Animal Consumption http://www.ofr.gov/OFRUpload/OFRData/2011-10953_PI.pdf
• Federal Register Notice for Interim Final Rule on Information Required in Prior Notice of Imported Food http://www.ofr.gov/OFRUpload/OFRData/2011-10955_PI.pdf

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation's food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Media Inquiries: Doug Karas, 301-796-2805, douglas.karas@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

SOURCE U.S. Food and Drug Administration

The Questions On Telaprevir and Boceprevir

Paul Sax • April 28th, 2011

http://blogs.jwatch.org/hiv-id-observations/index.php/hepatitis-c-week-is-upon-us/2011/04/28

After many — and I mean many — years of telling patients that new hepatitis C drugs were “coming soon,” that time has finally come.

An FDA Advisory Panel yesterday favorably reviewed the HCV protease inhibitor boceprevir; today telaprevir got the same unanimous report. The FDA will  certainly follow with approval for both drugs, and hence they will be available for actual use soon.

While these are undoubtedly huge advances for patients with HCV genotype 1 — who faced a 30-40% chance of cure with IF/ribavirin now, compared with up to 80% by adding one of the new drugs — many questions remain about how they will be used, and in whom.
In no particular order, and without even trying to be comprehensive, here are some of the “known unknowns“:
,

• How will clinicians choose between them?
• Is a 4-week lead in with IF/RBV (as was done with the boceprevir studies) necessary?  Additionally, is it useful, by identifying “null” responders who will have a higher rate of developing treatment failure and PI resistance?  Could starting all three drugs simultaneously improve outcome?
• How long should treatment be?  Will this vary depending on HCV RNA kinetics from person-to-person?  Seems like this is a situation ripe for sophisticated modeling, and that  more frequent HCV RNA monitoring (especially early) will inform this decision.
• How will patients in the chaotic real world tolerate these drugs?  Interferon/ribavirin is already no picnic, and adding these additional meds will mean additional side effects.
• Related:  Besides the signature toxicities (telaprevir — rash and anemia, boceprevir — anemia and dysgeusia), what other side effects will appear with more widespread use?  Note that it’s not a question of if these side effects will occur, it’s when will occur, and what they will be.
• How will resistance be assayed?  Will genotype testing become commercially available?  If so, what new combination of letters and numbers (i.e. mutations) will need to be memorized?
• How do these advances influence treatment decisions about the patients who don’t have HCV genotype 1, especially those with genotype 4?  I suspect not at all, at least for now.
• How will compliance be with these three-times a day regimens?  Will it improve over the course of therapy, or will patients get “pill fatigue.”  We know they will get regular fatigue — I have yet to see a patient receiving interferon who didn’t mention this as a side effect.
• View from 20,000 feet:  If someone is currently very stable — with low risk of HCV disease progression — should they “act now” or wait for even better, less toxic options?  Given the huge effort in HCV drug development, how long before we have treatments for HCV that are comparably simple to HIV therapy?  Is a single-pill combination tablet too much to ask?  Remember, for HIV, such a treatment would have been unimaginable in 1996; less than 10 years later it was the mostly widely-used HIV combination in the country, and remains so today.
• Who will be the HCV Providers?  Will the legacy of gastroenterologists’ leading the way in hepatitis therapy continue, or will this Infectious Disease finally be embraced by Infectious Disease Doctors?  (Italics represent my view.)
• How much will the new drugs cost?  Will they be covered for all patients?  How about for those who have a favorable IL-28B genotype — and would be likely responders to IF/RBV alone?
• How will our HIV co-infected patients respond?  Data are extremely limited — and the drug-drug interactions promise to be unbelievably complex.  As of April 28 2011, we only have data on use of telaprevir with either EFV or ATV/r.
• How do you design an HCV clinical trial once these drugs are approved?  Will all “control” arms now need to be IF/RBV + something-previr?

Answers to some of these questions will come with formal FDA approval, which will necessarily include some “package insert” indications for therapy.
But stay on your toes, because it seems highly likely that this is one therapeutic area in ID that truly lends itself to the cliche, “moving target.”

NPR ;What's In Your Painkiller? and Study Muddies Water On Health Effects Of Salt

NPR today published an article on Acetaminophen and other painkillers. The article notes that researchers found in a study of six focus groups that out of 45 people only 31 percent knew that in Tylenol acetaminophen is the active ingredient. 

At the same time, three-quarters identified aspirin as the active ingredient in Bayer aspirin. A little less than half — 47 percent — said ibuprofen was in Motrin, 19 percent said Aleve contained naproxen sodium, and 19 percent said that ibuprofen was in Advil.

Michael S. Wolf, a professor of medicine at Northwestern and senior author of the study, says he was most surprised that only 41 percent of study participants said they always look at ingredient information when buying over-the-counter drugs. The results appear in the latest issue of the journal American Journal of Preventive Medicine.

Read the full article here

Also on the NPR site ; Study Muddies Water On Health Effects Of Salt

A provocative study in the latest issue of JAMA suggests that moderate salt intake might be no problem and that for many people diets very low in salt could be a recipe for trouble.

European researchers studying nearly 4,000 people as they aged found increases in systolic blood pressure were associated with increases in salt measured in the urine. (Sorry, that's how the researchers could accurately quantify how much salt people had in their systems.)

 

Changes in diastolic blood pressure (the bottom number in blood pressure readings) didn't show a relationship with salt.
And, perhaps most interesting of all, the increases in salt and diastolic pressure were not associated with an increase in deaths from cardiovascular disease, such as heart attacks and strokes. Indeed, people with less salt in their urine were more likely to die from cardiovascular causes.

Surprising, right? Previous research has predicted, for instance, that lowering salt intake just a little — a half-teaspoon a day — would save the lives of at least 44,000 Americans a year.

Read The Full Study Here