LC2016/Short treatment with sofosbuvir and ledipasvir over only six weeks is sufficient to cure acute Hepatitis C

Scientists find a way to cure Hepatitis C with six weeks of treatment
April 16, 2016
Press Releases

Short treatment with sofosbuvir and ledipasvir over only six weeks is sufficient to cure acute Hepatitis C (HCV) 

April 16, 2016, Barcelona, Spain: A pilot study presented today found that all patients with acute HCV who were treated with a direct-acting antiviral treatment over a ‘short-duration’ of six weeks had undetectable HCV after a 12 week follow-up. The investigator-initiated study, presented at The International Liver CongressTM in Barcelona, Spain, demonstrated that the combination of sofosbuvir and ledipasvir for only six weeks is sufficient to treat patients with acute HCV.

Those infected with HCV usually develop acute Hepatitis C, which spontaneously clears in 10 to 50% of infected persons. Early diagnosis of HCV infection is rare and the disease may go unnoticed until patients have already developed serious liver damage.1 Sofosbuvir and ledipasvir is one possible regimen for treatment of patients with chronic HCV. Sustained virologic response (SVR) is greater than 95% with a 12-week course of this treatment.2

“Given the high cost of sofosbuvir and ledipasvir, and the associated side effects that occur during treatment, we set out to assess whether shortened treatment duration could be an effective option for acute Hepatitis C patients,” said Katja Deterding from Hannover Medical School, Germany and study author. “Our research demonstrates that not only is the combination of sofosbuvir and ledipasvir safe, well tolerated and effective in acute HCV genotype 1 patients who have severe liver disease with very high liver enzymes, but a shorter treatment duration does not appear to hinder efficacy,” confirmed Professor Heiner Wedemeyer, the senior author of this study.

The German pilot study, performed by the German HepNet Study-House included 20 patients. Risk factors of HCV infection among the study members included; sexual transmission (n=11), medical procedures/needle stick injury (n=5), drug use (n=1), and nail treatment complications (n=1). The causes were unspecified for the remaining two patients.

All 20 patients completed six weeks of sofosbuvir and ledipasvir without ribavirin. At the 12 week follow up, all 20 patients had undetectable HCV and achieved SVR (100%). Fatigue was the most frequent side effect reported by study members (30%).

“These exciting findings open up short and cost-effective treatment options that could prevent the spread of HCV in high risk populations,” said Professor Frank Tacke, EASL Governing Board member. “We look forward to seeing this pilot study extended so the findings can be validated and then hopefully used as a tool to change clinical practice for the better.”

Starting Treatment of Acute HCV Early: Is This the Best Option?

Starting Treatment of Acute HCV Early: Is This the Best Option?
David E. Kaplan, MD, MSC

Medicine and Research Services, Corporal Michael J. Crescenz VA Medical Center, Philadelphia PA; Division of Gastroenterology, Department of Medicine, University of Pennsylvania.

This article was published in the August/September 2015 issue of AGA Perspectives.

Acute hepatitis C continues to be encountered less frequently in routine GI clinical practice, except in relatively well-defined hot spots. The majority of acute hepatitis C cases are asymptomatic and usually escape early detection unless due to surveillance or luck, when abnormal liver enzyme tests are found. Symptomatic cases may manifest such protean symptoms that mild associated jaundice goes unnoticed by both patients and health-care providers alike.

Read more..

CDC Underestimates Number of Acute HCV Infections

CDC Underestimates Number of Acute HCV Infections
Lara C. Pullen, PhD
July 07, 2015

Source - Medscape

Formal surveillance by the Centers for Disease Control and Prevention (CDC) does a poor job of measuring the clinical diagnosis of acute hepatitis C virus (HCV) infection, according to a new report. Case ascertainment is negatively affected by incomplete clinician reporting, limitations of diagnostic testing, problematic case definitions, and imperfect data capture, and these problems persist despite automated electronic laboratory reporting.

Shauna Onofrey, MPH, from the Massachusetts Department of Public Health in Jamaica Plain, and colleagues published the results of their case series and chart review online June 30 in the Annals of Internal Medicine. The investigators reviewed medical records from two hospitals as well as a state correctional healthcare system in an effort to validate estimates of the incidence of acute HCV infection in their state.

Theirs was not a population-based survey of acute HCV infection, and thus they did not have an overall denominator with which to calculate incidence of disease.

The investigators identified 183 patients who were clinically diagnosed with acute HCV infection from 2001 to 2011. The majority (81.4%) of these patients were reported to the Massachusetts Department of Public Health for surveillance classification.

During that time, less than 1% of these cases were reported to the CDC, and the majority of the cases did not match the national case definition of acute infection. Reporting was also incomplete because of the requirements for negative hepatitis A and B laboratory results.

The authors had some suggestions to improve surveillance: "we agree with the decision to add seroconversion to the CDC's surveillance case definition of acute HCV infection in late 2012 to account for incident cases without need for an illness compatible with HCV infection, a criterion that is often absent, and to remove the requirement for negative test results for hepatitis A and B virus. Successful application of seroconversion as a criterion requires regular interval testing of high-risk patients. More detailed risk behavior history about specific injection practices and history of onset was extremely useful in a systematic screening for HCV infection in the Massachusetts state prison system, tripling the rate of identification."

In 2010, 850 acute HCV cases were reported to the CDC by local health authorities, and the CDC used this number to estimate a total of 17,000 cases annually. The current study suggests this is an underestimate.

Moreover, the lack of reported surveillance cases in Massachusetts stands in stark contrast to a growing HCV infection epidemic among adolescents and young adults in the state.

One coauthor reports receiving personal fees from AbbVie Pharmaceuticals outside the submitted work. Another coauthor reports receiving grants from the CDC during the conduct of the study. Dr. Kim reports receiving grants from the National Institutes of Health, personal fees from Bristol-Myers Squibb, and grants and personal fees from AbbVie Pharmaceuticals and Gilead Sciences during the conduct of the study. The other authors have disclosed no relevant financial relationships.

Ann Intern Med. Published online June 30, 2015. Abstract

Related-
Hepatitis C - Rise in heroin use drives needle exchange programs

Some patients with HCV may benefit from delayed treatment initiation

Some patients with HCV may benefit from delayed treatment initiation

Deuffic-Burban S. J Hepatol. 2012;57:260-266.

Aug 17 2012

Delayed initiation of treatment may be beneficial for patients with HCV detected more than 2 months after transmission, according to recent results.

Researchers designed a model to compare three treatment initiation methods in patients with acute HCV: immediate (within 2 months of transmission); early (within 3 months) and delayed (within 4 to 5 months). The model incorporated data from a separate study which evaluated outcomes in patients with acute HCV according to the presence of clinical symptoms; and a study in which the efficacy of early treatment was measured.

The likelihood of a patient achieving SVR was estimated at 92.6% with treatment initiated within 2 months of transmission, 76.5% within three months and 78.6% within 4 to 5 months. A 50% frequency of the C/C genotype was assumed, along with an increased likelihood of HCV clearance among patients with this genotype (OR=0.38) compared to those without it. Investigators used this model to estimate the probability of developing chronic HCV after 18 months under each treatment method, according to the presence of clinical symptoms and the C/C IL28B genotype.

Immediate initiation was linked to a lower probability of developing chronic HCV for both symptomatic (7.1% of those with C/C genotype, 7.3% of those without) and asymptomatic (6.6% with and 7.1% without) patients compared with delayed initiation, for which researchers estimated probabilities of 13.5% with C/C genotype and 18.0% without among symptomatic patients; and 14.6% with and 18.5% without C/C among asymptomatic patients. Higher probabilities for chronic HCV were estimated for early initiation, with 22.5% of C/C and 23.1% of non-C/C symptomatic patients developing the illness, along with 21.1% of C/C and 22.5% of non-C/C asymptomatic patients.

“Regardless of IL28B polymorphism, in asymptomatic or symptomatic patients in whom [acute HCV] is detected within 2 months of HCV transmission, it is preferable to propose immediate antiviral therapy,” the researchers wrote. “In patients in whom acute HCV transmission is detected more than 2 months after transmission, treatment 4 or 5 months later may be preferred because of higher rates of spontaneous HCV clearance after 2 months and almost similar HCV treatment efficacy between months 3 and months 4-5; again, regardless of symptomatic or non-symptomatic nature of the disease and IL28B polymorphism.”

Disclosure: See the study for a full list of relevant financial disclosures.

http://www.healio.com/hepatology/viral-hepatitis/news/online/%7BC0278190-4C68-4828-9CC3-E6AD1942C0CB%7D/Some-patients-with-HCV-may-benefit-from-delayed-treatment-initiation

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

Does Acute HCV Affect the Central Nervous System in HIV-1 Infection?

Does Acute HCV Affect the Central Nervous System in HIV-1 Infection?

Authors and Disclosures

See Full Test:
Abstract and Introduction
Methods
Results
References
Free Registration Required

Discussion

Acute HCV infection is a condition that has hitherto been unrecognized by medicine, as HCV-infected individuals normally present after a lag period of many years following initial infection. Given the rarity of its presentation, this is the first study to assess the effects of acute HCV infection on the central nervous system. We have observed significant reductions in RBG mI/Cr ratio in HIV-1 infected subjects with acute HCV infection, compared with that in matched groups of HIV-1 infected subjects without HCV infection and in healthy controls. Furthermore, significant abnormalities in neurocognitive function were observed.

The fall in mI/Cr ratio that we have observed was predominantly secondary to a reduction in mI in subjects with acute hepatitis C, although there was a trend towards a raised Cr in this group also [mI (±SD) of 121 (±13) vs 129 (±11) and 130 (±10) and Cr (±SD) of 44 (±8) vs 38 (±4), 39 (±5) in groups 1 vs 2 and 3, P = 0.049 and 0.143 respectively]. Other groups have described altered cerebral metabolite patterns in chronic HCV, rather than acute HCV, with differing results including elevation of basal ganglia and central white matter Cho,[2,16,29] reductions in grey and white matter NAA[5,29] and, of note, increases in FWM mI/Cr ratio.[20]

We have utilized the jMRUI software package which uses the AMARES algorithm to analyse our data.[27] This algorithm has several advantages such as the programming of prior knowledge to analyse data which reduces operator-dependent variability.[30] Forton et al.,[20] utilizing a similar analytical method, also observed changes in mI/Cr ratio in patients with chronic HCV, but reported an increase in this ratio in the FWM, rather than the reductions in mI/Cr that we found in patients with acute HCV. mI is an osmosensitive glial marker and plays a crucial role in cell volume regulation.[31] Organic osmolytes, such as mI, accumulate inside the cell in response to cell shrinkage, and are rapidly released in response to cell swelling via osmoregulated membrane channels.[32,33] Our findings are novel in patients with acute viral infections, as a low mI/Cr ratio has previously been observed only in patients with end-stage liver disease with established cirrhosis and hepatic encephalopathy, where there are varying degrees of cerebral oedema in response to the presence of unfiltered circulating toxins, such as ammonia, with subsequent regulatory lowering of mI levels in an effort to maintain astrocyte osmotic equilibrium, as the brain swells.[34] Clearly, this is not the mechanism in our cohort with documented acute HCV infection, who may be up to 30 years away from developing HCV-related end-stage liver disease, if their viral infection persisted. We hypothesize that the reduction in mI/Cr ratio we have observed may be an early response to the direct effects of HCV on the CNS and could suggest an initial cellular swelling as part of the acute neuroinflammatory response to the presence of the HCV.

Previous reports have described significant changes in cerebral metabolite patterns in HIV-1 infected subjects with AIDS Dementia Complex, such as an increase in mI in FWM.[35,36] We did not observe any differences between groups 2 and 3 in our study, which is likely to reflect the exclusion of any baseline neurological disease from inclusion in this study. Furthermore, the mean CD4+ lymphocyte count in the HIV-1 mono-infected group was high at 392 cells/μL (SD ± 124), with 60% of subjects on ART; both factors associated with a reduced incidence of HIV-1 related brain injury.

In HIV-1 non-infected subjects with chronic HCV infection, studies have suggested that up to one-third of subjects have CNS dysfunction.[20] We have observed a mI/Cr ratio below the lowest value in 50% of subjects in our control population. Although small numbers are represented, the relatively high proportion of subjects with evidence of HCV-associated CNS disease may be related to the acute nature of the infection, with a more aggressive inflammatory response, or viral replication, or may reflect a greater propensity for CNS dysfunction in HIV-1 infected subjects. It has been postulated that the effects of HCV on the CNS may be because of cerebral immune activation[37] or direct viral replication.[15] In the context of HIV disease, both of these processes may occur at increased rates.

Chronic fatigue has been well described in chronic HCV infection.[29] In this study, we describe a significant reduction in the monitoring domain with a large effect size of this association (r-value >0.28).[28] This may be associated with fatigue and an inability to concentrate on a task in the setting of acute HCV. No significant associations were observed directly between this cognitive test and cerebral metabolites, which may be related to small study numbers.

Abnormal cerebral metabolism has been documented in recreational drug-dependent subjects[38] and may confound results in studies assessing CNS function in HCV. We therefore excluded subjects currently using recreational drugs, thereby eliminating this bias and we excluded subjects with other sexually transmitted infections which are known to cause CNS disease, such as early syphilis.

This study is the first report to describe significant effects of acute HCV infection on the CNS in HIV-1 infected subjects. Clinicians should be vigilant for the early onset of the CNS effects associated with HCV infection, particularly in those co-infected with HIV. Further studies are required to put these results into context, including cerebral positron emission tomography with the specific ligand [11C](R)-PK11195 as a marker of microglial activation,[39] and there is a need for treatment programmes which monitor viral eradication in acute HCV infection to incorporate assessment of these imaging and psychometric parameters to look for resolution over time of the CNS observations that we have reported.
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Acute Hepatitis C Infection Surveillance

From Morbidity & Mortality Weekly Report

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Evaluation of Acute Hepatitis C Infection Surveillance — United States, 2008
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RM Klevens, DDS; RA Tohme, MD
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Authors and Disclosures
Posted: 12/20/2010; Morbidity & Mortality Weekly Report. 2010;59(43):1407-1410. © 2010 Centers for Disease Control and Prevention (CDC)

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Abstract and Introduction
Reporting of Acute Hepatitis C Cases through NNDSS
Reporting of Acute Hepatitis C Cases through EIP Sites
Comparison of NNDSS and EIP Surveillance
Editorial Note
References

Abstract and Introduction
Introduction
Hepatitis C virus (HCV) infection affects nearly 4 million persons and causes an estimated 12,000 deaths each year in the United States.[1] For the 10-year period from 2010 to 2019, the direct medical cost of chronic HCV infection is projected to exceed $10.7 billion, the societal cost of premature mortality attributed to HCV infection is projected to be $54.2 billion, and the cost of morbidity from disability associated with HCV infection is projected to be $21.3 billion.[2] The Institute of Medicine recently recommended a comprehensive evaluation of the national hepatitis B and C surveillance system.[3] Complete and timely surveillance data are essential for early identification and response to outbreaks and for implementation of evidence-based prevention strategies. To assess these attributes, CDC compared acute hepatitis C surveillance data reported in 2008 from the National Notifiable Diseases Surveillance System (NNDSS) and the Emerging Infections Program (EIP), which conducts enhanced surveillance for acute hepatitis C in selected states. This report summarizes the results of that analysis, which indicated that 26 (22%) of 120 cases reported from EIP-funded sites were missing from NNDSS. Data on race and major HCV risk factors were missing from 22% and 60% of reports in NNDSS, compared with 8% and 25% of reports in EIP, respectively. The mean duration between diagnosis and reporting of the case to the state health department was 30 days (range: 0–298 days) in NNDSS compared with 19 days (range: 0–350 days) in EIP sites. These findings underscore that enhanced surveillance for acute hepatitis C improves the completeness and timeliness of the data.

Reporting of Acute Hepatitis C Cases through NNDSS
Health-care providers, hospitals, and laboratories are required to send reports of cases of HCV infection to state and local health departments that include them within their jurisdiction. Reports meeting the Council of State and Territorial Epidemiologists (CSTE) and CDC case definition for acute hepatitis C* are entered into each state's notifiable disease surveillance system. States voluntarily transmit case reports to CDC on a weekly basis via the National Electronic Telecommunications System for Surveillance (NETSS).† NETSS is a system of computerized record formats used to transmit NNDSS data from health departments to CDC. The NETSS case reporting form includes data on demographics (e.g., age, date of birth, sex, race, and ethnicity), clinical information (e.g., date of onset, date of diagnosis, jaundice, hospitalization, and death), and risk factor exposures occurring 6 weeks to 6 months before illness onset (e.g., injection-drug use, sexual/household contact with a person with hepatitis, blood transfusion with dates of transfusion, dialysis, needle stick, tattoo, surgery, acupuncture, and being a health-care worker who has contact with human blood). Laboratory results are not transmitted to CDC because the electronic infrastructure in NETSS does not include fields for laboratory findings.

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* Available at http://www.cdc.gov/ncphi/disss/nndss/casedef/hepatitiscacutecurrent.htm.† Additional information available at http://www.cdc.gov/ncphi/disss/nndss/netss.htm.

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Reporting of Acute Hepatitis C Cases through EIP Sites
EIP hepatitis surveillance§ collects more extensive information compared with NETSS. In addition to demographics, the EIP form includes clinical data (e.g., date of diagnosis, symptoms, jaundice, hospitalization, pregnancy, death from hepatitis, liver function tests, hepatitis laboratory test results, and reason for testing) and risk factor exposures occurring 2 weeks to 6 months before illness onset (i.e., contact with a person with hepatitis and the type of contact, number of male and female sex partners, previous history of treatment for sexually transmitted diseases, use of illicit drugs [both injection and noninjection], hemodialysis, injury with sharp object contaminated with blood, blood/blood products transfusion with dates of transfusion, receipt of intravenous infusions and/or injections in outpatient settings, exposure to blood, medical/dental/public safety worker employment with frequency of exposure to blood, presence of tattoo/piercing and location where they were performed, dental work/surgery, hospitalization, residence in a long-term–care facility, and incarceration). In 2008, six EIP sites (Connecticut, Colorado, Minnesota, Oregon, 34 counties in New York State, and New York City) were funded by CDC to conduct enhanced acute hepatitis C surveillance. The catchment area of these sites comprises approximately 28 million persons. Site staff members investigate physician and laboratory reports submitted to health departments and directly contact the health-care providers to complete the demographic, clinical, and risk factor information listed in the EIP case reporting form; reports that fulfill the acute HCV infection case definition are sent monthly to CDC.

Additional information available at http://www.cdc.gov/ncpdcid/deiss/eip/index.html.

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Comparison of NNDSS and EIP Surveillance
Cases reported to NNDSS and EIP were matched by a common case identifier and date of birth. CDC evaluated data quality by measuring the completeness of information on demographic and clinical variables, including age, sex, race, ethnicity, jaundice, and major HCV infection risk factors, in both NNDSS and EIP systems. Sensitivity and positive predictive value of NNDSS for reporting acute hepatitis C cases were calculated for the sites conducting both NNDSS and EIP surveillance by using EIP sites' surveillance as the reference. Timeliness of case reporting was based on calculating the interval between the date of diagnosis and the date of reporting of the case to the state health department.

In 2008, a total of 877 cases of acute hepatitis C were reported to CDC by NNDSS via NETSS from 40 states. A total of 120 cases were reported from the six EIP sites; in comparison, 102 cases were reported from NNDSS in states that also are funded for EIP. Although age and sex data were nearly complete in NNDSS and EIP sites, race and ethnicity were missing in 22% and 41% of reports in NNDSS, compared with 8% and 21% in EIP, respectively. Completeness of demographic information for cases of acute hepatitis C in NNDSS was substantially higher in the six sites that also have an EIP surveillance system in place, compared with the remaining states that are not funded for enhanced surveillance (Table 1). Presence or absence of jaundice was reported in 63% of cases from NNDSS and 98% of cases reported from EIP. Completeness of information on major HCV infection risk factors ranged from 15% to 46% for NNDSS, compared with 70% to 77% in EIP sites. Completeness of clinical and risk factor indicators did not differ substantially in NNDSS when comparing states that have EIP surveillance to those that are not part of EIP.

Comparison of the cases that were reported from NNDSS and in the six sites funded for EIP surveillance revealed that 26 cases reported in EIP were missing from NNDSS; however, only eight cases that were reported to NNDSS were not reported to EIP (Table 2). Considering EIP as the reference, sensitivity and positive predictive value of NNDSS were 78% (94 of 120) and 92% (94 of 102), respectively.

Complete information on both the date of acute hepatitis C diagnosis and date of case reporting to the state health department was available for 39 cases (4%) in NNDSS and 72 cases (60%) in EIP sites. The mean duration between diagnosis and reporting of the cases to the state health department was 30 days (range: 0–298 days) in NNDSS, with 74% and 77% of the cases being reported within 7 days and 1 month of diagnosis, respectively. Among EIP sites, the mean duration between diagnosis and reporting of the cases to the state health department was 19 days (range: 0–350 days), with 80% and 94% of the cases being reported within 7 days and 1 month of diagnosis, respectively.

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Editorial Note
The findings in this report show that the quality of data from NNDSS is not on par with data reported from EIP surveillance sites. Clinical and risk factor information for a substantial proportion of the cases was missing from NNDSS. As shown in previous studies, NNDSS had a substantial proportion of cases with missing data on race and ethnicity.[4,5] Hepatitis C disproportionately affects non-Hispanic blacks compared with persons of other races.[1] Therefore, surveillance data should include race and ethnicity information to reduce disparities through targeted prevention programs.[4] In addition, because of limited resources, several states are not able to handle the volume of laboratory case reports received, which affects timeliness of reporting. In 2009, a total of 27 jurisdictions had backlogs of HCV data, with an average of 6,200 reports that needed to be entered.[3] Accurate, timely, and complete surveillance data are needed to identify and respond to outbreaks in a timely fashion, to guide and evaluate prevention strategies, and to allow for the early initiation of treatment, leading to an ultimate decrease in health-care costs.

Health departments using EIP enhanced surveillance have shown its effectiveness in identifying clusters or outbreaks of hepatitis C infection. For example, the New York State Department of Health detected a cluster of 20 hepatitis C infections among young injection-drug users by conducting enhanced surveillance of HCV infections reported among persons aged <30 href="javascript:newshowcontent(">[6]
Similarly, EIP enhanced surveillance of acute hepatitis C infections allowed the identification of health-care–associated acute hepatitis C outbreaks.

Early identification of acute hepatitis C infection is essential to prevent chronic infections and subsequent liver cancer and associated health-care costs. In fact, early treatment of hepatitis C prevents chronic disease in more than 90% of persons treated during the acute phase of the infection[7,8] and more than doubles the chance of achieving a sustained virologic response (absence of HCV RNA 24 weeks after discontinuation of therapy reflecting absence of viremia and normal liver function), compared with that achievable by treating chronic hepatitis C infection.[9] The rate of achieving a sustained virologic response is inversely associated with time from acute HCV infection diagnosis.[9] In addition, early treatment contributes to lower health-care costs compared with later treatment.[8]

The findings in this report are subject to at least four limitations. First, the data for timeliness calculation were missing from the majority of NNDSS cases, and this might have led to an overestimation of timeliness in NNDSS. Second, estimates of timeliness would have been improved if CDC had been able to assess the duration between diagnosis and reporting to the local rather than the state health department. However, this information was not available from NETSS. Third, the states where enhanced reporting of acute hepatitis C was implemented were not selected at random; consequently, the observed differences between the performances of the NNDSS and EIP surveillance systems might not all be attributable to differences between the surveillance systems themselves. Finally, this report could not assess the proportion of missed diagnoses of acute HCV infections at the provider level, which would contribute to underreporting of cases to both NNDSS and EIP.

The comparison of NNDSS (a passive surveillance system) with EIP (an enhanced surveillance system) indicates that accuracy and timeliness of reporting for acute HCV infections were improved through enhanced surveillance. Expanding enhanced surveillance for acute hepatitis C to the national level would detect an estimated additional 22% of acute hepatitis C cases. However, because of budget constraints, enhanced surveillance for acute HCV infections is not implemented nationwide.

The Institute of Medicine report recommended a surveillance system comparable to that of human immunodeficiency virus (HIV) surveillance.[3] HCV and HIV infections are similar in that many of the cases are asymptomatic and early identification and initiation of treatment would prevent transmission, complications, and deaths. However, although HIV case ascertainment requires a single laboratory test, ascertainment of a single case of acute HCV infection requires an average of four laboratory reports.[10] Based on the findings described in this report, additional resources for acute hepatitis C surveillance could enhance substantially the quality of the data on which prevention interventions are based, and in turn, could reduce morbidity and mortality associated with HCV infection. Nonetheless, a cost-benefit analysis to assess the usefulness of implementing EIP enhanced surveillance for acute hepatitis C at the national level is needed.