July 10, 2011

Hepatogastroenterology. 2011 Mar-Apr;58(106):551-7.

Chen WT, Macatula TC, Lin CC, Lin CJ, Lin SM.

Division of Hepatology, Liver Research Unit, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan.

Abstract

BACKGROUND/AIMS: Diabetes mellitus (DM) is prevalent in patients with hepatocellular carcinoma (HCC) but its effects on post-radiofrequency ablation (RFA) have not been elucidated. This study aims to determine whether DM significantly impacts the outcomes in patients with HCC after RFA.

METHODOLOGY: This retrospective study included 161 HCC patients successfully treated with RFA. Intra-hepatic HCC recurrence and survival were analysed.

RESULTS: No significant difference was found for 1-, 2-, 3- year's intra-hepatic HCC recurrence rates (DM: 45%, 61%, 74% vs. non-DM: 42%, 62%, 75%;p=0.935) and survival rates (DM: 83%, 80%, 73% vs. non-DM: 92%, 84%, 79%; p=0.218) between diabetics (53 patients) and non-diabetics (108 patients). In subgroup analysis of viral etiology and HCC, no significant difference was noted for intra-hepatic HCC recurrence or survival in hepatitis B virus-related or hepatitis C virus-related HCC. Multivariate analysis showed only persistent hepatitis influenced intra-hepatic HCC recurrence (p=0.021) and survival (p=0.022).

CONCLUSION: DM may not affect the intra-hepatic HCC recurrence and survival in patients with HCC after RFA. However, persistent hepatitis after RFA may affect intra-hepatic HCC recurrence and survival.

Source
J Hepatol. 2011 Jun 30. [Epub ahead of print]

Asselah T.

Service d'hépatologie, Hôpital Beaujon, Clichy, France and INSERM, U773, Centre de Recherche Bichat-Beaujon CRB3, and University Paris Diderot.

Abstract

BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.

METHODS: To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks.

RESULTS: A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls.

CONCLUSIONS: The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500).

Copyright © 2011. Published by Elsevier B.V.

Source

Noninvasive tests predicted survival in chronic hepatitis C

Posted on HemOncToday.com July 8, 2011

Vergniol J. Gastroenterology. 2011;140:1970-1979.

Noninvasive tests for fibrosis and liver stiffness predicted 5-year survival in patients with chronic hepatitis C, according to researchers from CHU Bordeaux in France.

“The evaluation of liver fibrosis is a key step to manage a chronic liver disease and to assess its prognosis, as complications mainly occur in patients with advanced stages,” the researchers wrote. “Early assessment of the risk of bad prognosis helps the physician to manage patients with cirrhosis and to make decisions about liver transplantation.”

The researchers prospectively collected data from a cohort of 1,457 consecutive patients who presented with chronic hepatitis C from April 2003 to February 2009. The patients’ fibrosis and liver stiffness were measured using the FibroTest, the aspartate aminotransferase-to-platelet ratio index and the FIB-4. Some patients also received liver biopsies. During the follow-up period, the researchers analyzed data on death, liver-related death and liver transplantation.

At 5 years, the overall survival was 91.7%, and survival without liver-related death was 94.4%. Among patients diagnosed with severe fibrosis at baseline, the survival was significantly decreased. Although all methods used were able to predict shorter survival, liver stiffness and the FibroTest had higher predictive values. After adjustment for treatment response, patient age and estimates of necroinflammatory grade, the prognostic value of liver stiffness (P<.0001) and FibroTest results (P<.0001) remained.

“In this prospective study, we confirmed the prognostic value of liver stiffness and FibroTest on survival,” the researchers wrote. “This information is of major importance, helping us to sharpen our various tools for the follow-up of our patients.”

Source

July 7, 2011

Gastroenterology. 2011 Jul;141(1):119-27. Epub 2011 Mar 24.

Chevaliez S, Hézode C, Soulier A, Costes B, Bouvier-Alias M, Rouanet S, Foucher J, Bronowicki JP, Tran A, Rosa I, Mathurin P, Alric L, Leroy V, Couzigou P, Mallat A, Charaf-Eddine M, Babany G, Pawlotsky JM.

National Reference Center for Viral Hepatitis B, C and delta, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France.

Abstract

BACKGROUND & AIMS: In patients with chronic hepatitis C who failed to respond to standard therapy, high-dose pegylated interferon (IFN)-α and/or ribavirin could induce a stronger antiviral response and prevent treatment failure and HCV resistance when combined with direct-acting antivirals. The influence of genetic determinants in this context remains unknown.

METHODS: Eighty-three patients infected with HCV genotype 1 who were nonresponsive to standard therapy received pegylated IFN-α2a (360 μg once per week or 180 μg twice per week) with ribavirin (1.0-1.2 or 1.2-1.6 g/d) for up to 72 weeks. Virological responses were assessed at different time points, and the influence of the IL-28B genotype was studied.

RESULTS: At weeks 12 and 24, respectively, 47 (56.6%) and 50 (60.2%) patients achieved a ≥2-Log(10) decrease of HCV RNA levels; 8 (9.6%) and 21 (25.3%) patients had undetectable HCV RNA after 12 and 24 weeks of treatment, respectively. Patients with a CT IL-28B genotype responded significantly better and earlier than those with a TT genotype. In multivariate analysis, the IL-28B genotype was an independent predictor of the virological responses at weeks 4, 12, and 24.

CONCLUSIONS: High-dose pegylated IFN-α with standard or high doses of ribavirin induces a potent antiviral response in a substantial number of patients who did not respond to standard therapy. The IL-28B genotype is an independent predictor of the antiviral response. High-dose pegylated IFN-α in combination with ribavirin and protease inhibitors appears as an attractive option for future study in this population.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Source
Dig Dis Sci. 2011 Jun 30. [Epub ahead of print]

Solomon M, Bonafede M, Pan K, Wilson K, Beam C, Chakravarti P, Spiegel B.

Stanford University School of Medicine, Stanford, CA, USA.

Abstract

BACKGROUND: Hepatitis C virus (HCV) is a common and expensive infectious disease. The current standard of care for HCV infection, pegylated interferon with ribavirin (PEG-RBV), is costly and has a significant adverse event profile.

AIM: To quantify the direct economic burden of HCV infection and PEG-RBV treatment for HCV.

METHODS: Using a large administrative claims database, we evaluated the medical and prescription drug costs of patients with HCV from 2002 to 2007. A cohort of patients with PEG-RBV was 1:1 propensity score-matched to a cohort of untreated HCV patients. Multivariate models adjusted for demographic and clinical characteristics in evaluating the effect of PEG-RBV treatment on direct medical expenditure.

RESULTS: The matched analysis included 20,002 patients. PEG-RBV-treated patients had higher total direct medical costs ($28,547 vs. $21,752; P < 0.001), outpatient pharmacy costs ($17,419 vs. $2,900; P < 0.001), and outpatient physician visit costs ($894 vs. $787; P < 0.001), but lower inpatient costs ($3,942 vs. $9,543; P < 0.001) and emergency room costs ($366 vs. $505; P < 0.001). After multivariate adjustment, PEG-RBV use was associated with an additional $9,423 in total direct medical costs and an additional $12,244 in HCV-related total medical costs.

CONCLUSION: Total HCV-related medical costs are higher for treated than untreated patients, driven mostly by higher outpatient pharmacy costs, which outweigh higher HCV-related inpatient costs incurred by untreated patients.

Source
J Hepatol. 2011 Apr 13. [Epub ahead of print]

Deltenre P, Louvet A, Lemoine M, Mourad A, Fartoux L, Moreno C, Henrion J, Mathurin P, Serfaty L.

Service d'Hépato-Gastroentérologie, Hôpital Huriez, CHRU Lille, Lille, France; Service d'Hépato-Gastroentérologie, Hôpital de Jolimont, Haine-Saint-Paul, Belgium.

Abstract

BACKGROUND/AIMS: Recent studies suggested that SVR rates might be lower in HCV patients with insulin resistance (IR) than in patients without IR, but the extent of the impact of IR on treatment response has not been established. We aimed to confirm the role of IR assessed by the homoeostasis model assessment (HOMA-IR) on SVR and to assess its magnitude.

METHODS: We performed meta-analysis of studies evaluating the impact of IR in HCV patients treated with pegylated interferon and ribavirin.

RESULTS: Fourteen studies involving 2,732 patients were included. SVR was less frequent in patients with IR than in patients without IR (mean difference: -19.6%, 95% CI: -29.9% to -9.4%, p<0.001). In sensitivity analyses according to HCV-1 patients, patients with IR also less frequently attained a SVR than patients without IR (mean difference: -13.0%, 95% CI: -22.6% to -3.4%, p=0.008). In addition, the baseline HOMA-IR index was lower in responders than in non-responders (mean difference: -0.92, 95% CI: -1.53 to -0.32, p<0.001). In sensitivity analyses restricted to HCV-1 patients, the baseline HOMA-IR index remained lower in responders than in non-responders (mean difference: -0.63, 95% CI: -1.13 to -0.14, p<0.001).

CONCLUSIONS: HCV patients with IR have a 20% lower SVR than patients without IR. The baseline HOMA-IR index is a major determinant of SVR.

Copyright © 2011. Published by Elsevier B.V.

Source
J Hepatol. 2011 Apr 14. [Epub ahead of print]

Tillmann HL, Patel K, Muir AJ, Guy CD, Li JH, Lao XQ, Thompson A, Clark PJ, Gardner SD, McHutchison JG, McCarthy JJ.

Duke Clinical Research Institute and the Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA.

Abstract

Background IL28B polymorphisms have been associated with both treatment induced and spontaneous clearance of hepatitis C virus (HCV). We previously found that LDL cholesterol levels were higher in chronic hepatitis C (CHC) patients with the CC genotype at the rs12979860 polymorphism, located proximal to the IL28 gene. Here we analyzed the association of steatosis with IL28B genotype in treatment naïve patients with CHC. Methods Two independent cohorts of 145 genotype 1 infected patients from an antifibrotic study and 180 genotype 1 patients from Duke were analyzed for presence and severity of steatosis in relation to the rs12979860 polymorphism at the IL28B locus. TaqMan assay based genotyping classified three groups CC, CT and TT. Results CC genotype was associated with a lower prevalence of steatosis. In the antifibrotic study steatosis was found in 47.6% (50/105) of IL28B non-CC versus 22.5% (9/40; p=0.008) in CC patients. Similarly, steatosis was found in 67.4% (89/132) of non-CC patients compared to only 39.6% (19/48; p=0.001) of CC patients in the Duke cohort. Conclusions IL28B CC genotype is associated with less pronounced disturbances of lipid metabolism, as reflected both in serum lipoprotein levels and hepatic steatosis, in HCV infection.

Copyright © 2011. Published by Elsevier B.V.

Source
Hepatology. 2011 Jun 30. doi: 10.1002/hep.24503. [Epub ahead of print]

Marabita F, Aghemo A, De Nicola S, Rumi MG, Cheroni C, Scavelli R, Crimi M, Soffredini R, Abrignani S, De Francesco R, Colombo M.

INGM - Istituto Nazionale Genetica Molecolare Milano, Italy.

Abstract

Polymorphisms in the IL28B region are associated with spontaneous and treatment-induced viral clearance in Hepatitis C virus (HCV) infection. Nevertheless, it is unknown whether genetic variation at the IL28B locus influences the natural history of chronic HCV infection. Thus, we asked if an association between IL28B polymorphisms and liver fibrosis progression existed. We studied 247 consecutive patients with chronic HCV, an accurate estimate of the date of infection and a liver biopsy performed before any treatment. No patient had a history of alcohol abuse or co-infection with other viruses. We assessed the role of rs8099917 and rs12979860 polymorphisms and the effect of host and environmental factors on fibrosis progression. Blood transfusion (75%) was the main modality of infection. The median age at infection was 21 years and the median interval between infection and liver biopsy was 25 years. 129 patients (52%) were infected by HCV-1, 74 (30%) by HCV-2, 34 (14%) by HCV-3 and 10 (4%) by HCV-4. Bridging fibrosis/cirrhosis (Ishak≥4) was detected in 24% of patients. Age at infection had a marked effect on fibrosis progression by both a linear model and Cox-proportional hazard regression (P<2E-16). A 12.1% increase in the hazard of advanced fibrosis was estimated for each additional year at infection, suggesting that this is the major explanatory variable in this cohort. Male gender (P<0.05), HCV genotype 3 (P<0.001) and steatosis (P<0.05) were also associated to faster fibrosis progression. Conversely, the two IL28B polymorphisms had no impact on fibrosis progression. Conclusions: In HCV patients with known date of infection IL28B genotype was not associated with fibrosis progression rate or with the risk of developing advanced liver fibrosis. (HEPATOLOGY 2011.).

Copyright © 2011 American Association for the Study of Liver Diseases.

Source
Gastroenterology. 2011 Jun 12. [Epub ahead of print]

Gottwein JM, Scheel TK, Jensen TB, Ghanem L, Bukh J.

Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre and Department of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Denmark.

Abstract

BACKGROUND & AIMS: The hepatitis C virus (HCV) genotype influences efficacy of interferon (IFN)-based therapy. HCV protease inhibitors are being licensed for treatment of genotype 1 infection. Since there is limited or no data on efficacy against HCV genotypes 2-7, we aimed at developing recombinant infectious cell culture systems expressing genotype specific NS3 protease (NS3P).

METHODS: Viability of J6/JFH1- based recombinants with genotype 1-7 NS3P/NS4A was evaluated in Huh7.5 cells. Adaptive mutations were identified in reverse genetic studies. Efficacy of lead compound linear protease inhibitors VX-950 (telaprevir) and SCH503034 (boceprevir) and macrocyclic inhibitors TMC435350, ITMN-191 (danoprevir), and MK-7009 (vaniprevir) was determined in high-throughput infection assays.

RESULTS: For genotype(isolate) 2a(J6), 3a(S52), 5a(SA13), and 6a(HK6a) we developed culture systems producing supernatant infectivity titers of 3.5-4.0 log(10) FFU/ml. Against 2a(J6), 5a(SA13) and 6a(HK6a) all inhibitors showed similar efficacy; macrocyclic inhibitors had ~10-fold greater potency than linear inhibitors. However, compared to 2a recombinant J6/JFH1 efficacy against 3a(S52) was 16- to 70-fold lower for macrocyclic inhibitors and 2- to 7-fold lower for linear inhibitors. Testing of additional genotype 2a and 3a isolates showed that these differences were genotype specific. The resistance of 3a isolates was similar to J6/JFH1 with engineered resistance mutations originally observed for genotype 1 patients. In contrast, we found similar efficacy of NS5A inhibitor BMS-790052 and interferon-alfa2.

CONCLUSIONS: Novel HCV culture systems with genotype specific NS3P/NS4A revealed similar efficacy of protease inhibitors against genotype 2a, 5a, and 6a and comparatively low but varying efficacy against genotype 3a isolates. These systems will facilitate genotype specific studies of HCV protease inhibitors and of viral resistance.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Source
By Kellee Terrell
From The Body
July 6, 2011

Recently, the U.S. Food and Drug Administration announced the approval of two drugs for hepatitis C virus (HCV) treatment, Incivek (telaprevir) and Victrelis (boceprevir) -- the first new HCV therapies in 10 years. This news is exciting for many people living with HCV, but especially so for African Americans.

HCV, a blood-borne disease that damages the liver, affects almost 4 million Americans (many of whom are also living with HIV), and African Americans account for almost 22 percent of those cases. Historically, with older HCV therapies, African Americans haven't had much success. But these new drugs appear to significantly increase the odds that treatment will work. For instance, when Victrelis was studied specifically in African Americans, researchers found that the African Americans who took the drug along with standard HCV treatment showed a significant increase in the odds that their HCV infection would be treated and cured.

I spoke with Jonathan McCone, M.D., the lead researcher of the African-American cohort in which Victrelis was studied, about this breakthrough drug and the importance of getting screened for HCV.

Can you explain what HCV is and how one contracts it?

HCV is a disease caused by a virus that infects the liver. Essentially, the liver kills itself. In time, it can lead to permanent liver damage as well as cirrhosis, liver cancer and liver failure.

People who are at risk are people who received blood transfusions before 1992 (because labs were not checking for HCV in the blood before then), people who have gotten stuck with infected needles, intravenous drug users who share infected needles, and people who have received piercings and tattoos with used needles that are infected.

This basically is not a sexually transmitted disease, unless there is blood involved. [Editor's note: Blood can be involved during many types of sex or foreplay, including anal sex and fisting; even a small amount of blood entering a microscopic cut on the body can potentially put a person at risk for infection.] You don't get it by kissing or breathing. It's generally a blood-to-blood illness, but if it's not specially checked for, it's not picked up. That doesn't mean that damage isn't occurring.

Can you tell us a little bit about Victrelis?

Victrelis is the first new medicine in a decade that has been approved in treating HCV. It's a pill that must be taken three times a day along with the other treatment: a once-a-week interferon shot and another twice-a-day pill [whose generic name is ribavirin]. You need all three forms of medicine to reap the benefits of the treatment. Victrelis will not work without the other treatments.

The most important thing to know is that HCV can be cured. Before Victrelis, we were seeing overall cure rates of just 40 percent in Caucasian Americans and only 23 percent cure rates in African Americans. But when we added Victrelis, African Americans who didn't have cirrhosis of the liver improved two-fold.

Why would cirrhosis make a difference in the success of HCV treatment?

If someone has cirrhosis, advanced damage is occurring. The liver tries to fight the virus by releasing cells to attack it. But what ends up happening is that virus kills those cells, and then turns the cells into scar tissue. The more scar tissue, the harder it is for the liver to do what it's supposed to do. The more advanced the disease, the harder it is to treat HCV.

I've seen patients who didn't know they had HCV and for 20 to 30 years their livers were getting worse and worse. If your disease gets really advanced, you might need a liver transplant or end up dying. This is why you have to get tested and treated early.

What are some of the side effects of HCV therapy, including Victrelis?

The most common side effects from HCV treatment are fatigue, anemia, feeling like you have the flu, headache, depression, weight loss and being irritable. But the good thing is that when people begin therapy, doctors check for all of these side effects and know how to modify certain things.

With Victrelis, there have been some complaints about having a metallic taste, but from what we know, it's not an overwhelming taste.

How long does HCV therapy usually last?

Before Victrelis, therapy usually lasted for one year in hopes to achieve a cure. But we have found that when Victrelis was added, for most patients, therapy time was cut down to six months. That's half the time.

Yes, there are a lot of pills and side effects to deal with. But I tell my patients, "You don't have a virus that gives a cold, you have a virus that makes you get a liver transplant and will kill you. Now you only have to take it for six months to reduce your [HCV] viral load and even cure your disease so you can enjoy your life. That's worth it all."

Why have African Americans had such little success with past HCV therapies?

Genetics. People who have good configurations of [a gene called] IL28B have a higher chance of being cured of HCV when on therapy. And what we have found is that African Americans were most likely to have bad configurations of IL28B, so even when they adhered to the therapy and did everything right, the treatment was less likely to be successful.

But when Victrelis was added to the existing therapies, even the people who had bad configurations had a better chance of being cured than without Victrelis. This is why this is such great news for the African-American community.

Is there a vaccine for HCV?

No, there is no vaccine for HCV. There are vaccines for hep A and B, though.

This is why it's important to get tested and get tested early. It's estimated that 75 percent of people who have HCV don't even know they have it. They are walking around, feeling good, but little do they know that damage is being done to their liver.

Also, doctors need to do a better job in making sure that they screen people and stop assuming who they think are the usual HCV suspects. Just like, at the age of 50, people are receiving colonoscopies, baby boomers should be getting routinely checked at 50 [for HCV] too.

This transcript has been edited for clarity.

Kellee Terrell is the news editor for TheBody.com and TheBodyPRO.com.

Source

July 6, 2011

Universal screening for hepatitis C supported by patients

Posted on HemOncToday.com July 6, 2011

Coffin PO. BMC Infect Dis. 2011;doi:10.1186/1471-2334-11-160.
 
Patients with hepatitis C support universal screening for the disease, even if the testing is conducted without patient consent, according to researchers from the University of Washington in Seattle.

In the United States, there are 2.9 million to 3.7 million people with hepatitis C, and approximately 70% of them are unaware of their infection. Universal screening may help reduce this number; however, there have been few efforts to determine patients’ opinions on the topic.

“National guidelines recommend that testing for hepatitis C virus be limited to persons with identified risk factors, such as injection drug use, a blood transfusion prior to 1992, or elevated liver function tests,” the researchers wrote. “Although these recommendations are based on epidemiologic data and 1998 CDC guidelines, barriers to risk-based screening have resulted in inadequate detection of hepatitis C virus.”

The researchers conducted an anonymous, self-administered, cross-sectional survey of 233 outpatients at Harborview Medical Center in Seattle. They asked participants to define the importance of testing for hepatitis C virus compared with HIV and diabetes mellitus. Two hundred patients completed the survey.

Most patients (76%) said the hospital should test all of its patients for hepatitis C virus. In addition, 73.2% said the hospital should test all of its patients for HIV, and 68.3% said the hospital should test all of its patients for diabetes. Most patients, however, said it would not be OK for the hospital to automatically test for hepatitis C and HIV without telling the patient. In addition, 75.3% of patients said it is better to be tested without knowing about it than to not be tested at all. Universal testing without being informed of being tested or provided with negative results was preferred by 48% of the patients, whereas 37% preferred the chance to opt out of testing.

“We do not believe that these findings should immediately prompt health care providers or organizations to abandon efforts to inform patients and seek consent for testing,” the researchers wrote. “However, efforts to broadly screen populations for communicable diseases have met formidable barriers.”

Source
HUDDINGE, Sweden, July 6, 2011 /PRNewswire/ --
Medivir AB (OMX: MVIR), is an emerging research-based specialty pharmaceutical company focused on infectious diseases.

Medivir today announced that its investigational protease inhibitor TMC435 has received "Fast Track" designation by the U.S. Food and Drug Administration ("FDA") for the treatment of chronic hepatitis C (CHC) genotype-1 infection. This is based on TMC435's potential to address unmet medical needs in the treatment of CHC infection compared to currently approved therapies.

TMC435 may offer:

• High sustained virological response (SVR) rates in genotype-1 HCV-infected patients, including hard-to-treat subgroups

• Short treatment duration

• Favourable overall safety and tolerability profile

• A convenient once-daily (q.d.) dosing regimen

Furthermore, Medivir also confirms the intention to start a proof-of-concept oral, interferon-free phase 2 trial, investigating the combination of TMC435, a once daily NS3/4A protease inhibitor (PI) for the treatment of genotype-1 chronic hepatitis C virus (HCV) infection and Pharmasset's PSI-7977, a once daily nucleotide NS5B polymerase inhibitor. The phase 2 study, which is being managed by Tibotec Pharmaceuticals, will investigate the efficacy and safety of 12 weeks or 24 weeks of TMC435 150 mg q.d. in combination with PSI-7977 400 mg q.d. with or without ribavirin in prior null responders to peginterferon/ribavirin therapy. The primary endpoint of the trial will be sustained virological response at 12 weeks (SVR12).

Bertil Samuelsson, CSO, of Medivir commented, "We are delighted to have received the Fast Track designation for TMC435 from the FDA. This shows that TMC435, with its high safety profile, efficacy, short treatment duration and convenience of once daily dosing, is believed to have the potential to provide benefit over current treatments. We believe TMC435 has the potential to become a cornerstone of future direct-acting antiviral combinations for HCV therapy. We are thus very pleased over the clinical collaboration agreement Pharmasset announced today with Tibotec, and the coming start-up of a TMC435 combination trial with Pharmasset's once daily NS5B nucleotide inhibitor PSI-7977. This is one of several ongoing TMC435 combination trials and we expect the momentum to continue with regards to the development of TMC435."

About Fast Track

Fast Track is a process designed to facilitate the development, and expedite the review of drugs to treat serious diseases and to fill an unmet medical need. The purpose is to get important new drugs to the patient earlier. Fast Track addresses a broad range of serious diseases. "Filling an unmet medical need" is defined as providing a therapy where none exists or providing a therapy that may potentially be superior to existing therapy. If there are existing therapies, a fast track drug must show some advantage over available treatment, such as:

• Showing superior effectiveness

• Avoiding serious side effects of an available treatment

• Improving the diagnosis of a serious disease where early diagnosis results in an improved outcome

• Decreasing a clinically significant toxicity of an accepted treatment

A drug that receives Fast Track designation is eligible for some or all of the following:

• More frequent meetings with the FDA to discuss the drug's development plan and ensure collection of appropriate data needed to support drug approval

• More frequent written correspondence from the FDA about such things as the design of the proposed clinical trials

• Eligibility for Accelerated Approval, i.e., approval on an effect on a surrogate or substitute endpoint reasonably likely to predict clinical benefit

• Rolling Review, which means that a drug company can submit completed sections of its New Drug Application (NDA) for review by FDA, rather than waiting until every section of the application is completed before the entire application can be reviewed. NDA review usually does not begin until the drug company has submitted the entire application to the FDA

• Dispute resolution if the drug company is not satisfied with an FDA decision not to grant Fast Track status.

In addition, most drugs that are eligible for Fast Track designation are likely to be considered appropriate to receive a Priority Review.

Once a drug receives Fast Track designation, early and frequent communication between the FDA and a drug company is encouraged throughout the entire drug development and review process. The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients.

About TMC435

TMC435, an investigational CHC protease inhibitor currently in phase 3 clinical development, is a highly potent, selective and safe once-daily (q.d.) drug jointly developed by Tibotec Pharmaceuticals to treat chronic hepatitis C virus infections.

TMC435 is being developed in combination with PegIFN/RBV and in combination with Direct-acting Antiviral (DAA) agents without peginterferon and with or without ribavirin (RBV). In June 2011 the combination study of TMC435 with TMC647055, a non-nucleoside NS5B polymerase inhibitor being developed by Tibotec Pharmaceuticals, was initiated.

Three global clinical phase 3 response guided studies were initiated in early 2011 by Tibotec:

• TMC435-C208 or QUEST-1 includes approximately 375 treatment-naïve patients

• TMC435-C216 or QUEST-2 includes approximately 375 treatment-naïve patients

• TMC435-C3007 or PROMISE includes approximately 375 who have relapsed after prior interferon-based treatment

Phase 3 programs for TMC435 are also ongoing in Japan.

In parallel with the recent start of the global phase 3-studies, TMC435 is currently in a follow up phase in three phase 2b clinical trials (TMC435-C205, TMC435-C206 and TMC435-C215) in G1 treatment-naïve and in G1 patients that failed previous IFN-based treatment. More safety and efficacy data from the phase 2b trials will be presented at scientific meetings later in 2011.

For additional information from these studies, please see http://www.medivir.com and http://www.clinicaltrials.gov/

About Hepatitis C

Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The US Centers for Disease Control ("CDC") has reported that almost three million people in the United States are chronically infected with HCV.

About Medivir

Medivir is an emerging research-based specialty pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company's key pipeline asset is TMC435, a novel protease inhibitor is in phase 3 clinical development for hepatitis C and is partnered with Tibotec Pharmaceuticals. In June 2011, Medivir acquired the specialty pharmaceutical company BioPhausia to ensure timely commercialization of TMC435 in the Nordic markets, once approved.

Medivir's first product, the unique cold sore product Xerese™/Xerclear® was launched on the US market in February 2011. Xerese™/Xerclear®, which has been approved in both the US and Europe is partnered with GlaxoSmithKline to be sold OTC in Europe, Japan and Russia. Rights in North America, Canada and Mexico have recently been sold to Meda AB. Medivir has retained the Rx rights for Xerclear® in Sweden and Finland.

For more information about Medivir, please visit the Company's website: http://www.medivir.com/.

For more information about Medivir, please contact:

Medivir (http://www.medivir.com/):
Rein Piir, CFO & VP Investor Relations
Mobile: +46-708-537-292

M:Communications:
Peter Laing / Amber Bielecka / Katja Toon
Medivir@mcomgroup.com
+44(0)20-7920-2330

USA: Roland Tomforde
+1-212-232-2356

Source

July 5, 2011

Timothy R. Morgan, MD; Thomas R. O'brien, MD, MPH

Posted: 04/04/2011; Clin Gastroenterol Hepatol. 2011;9(4):293-294. © 2011 AGA Institute

Abstract and Introduction

Introduction

Peginterferon alpha and ribavirin treatment for 48 weeks leads to a sustained virological response (SVR) in 40%–50% of subjects infected with hepatitis C virus (HCV) genotype 1 or 4 (G1/4) while treatment for 24 weeks produces SVR in 70%–80% of patients infected with HCV genotype 2 or 3. The variability in response to treatment, especially between patients of different racial groups, suggested that human genetic variability might explain differences in treatment response and led to investigations of the role of host genetics in achieving an SVR.

Genome-wide association studies which examine the association between >500,000 single nucleotide polymorphisms (SNPs) and a disease of interest, have been exceptionally successful in finding SNPs associated with response to hepatitis C treatment. In 2009, 3 groups reported that SNPs located near the gene for interleukin-28B (IL28B) were strongly associated with the likelihood of achieving an SVR with peginterferon + ribavirin treatment.[1–3] IL28B encodes a protein that is also known as interferon lambda-3 (IFN-λ3), a type III interferon. The receptors for interferon alpha, a type I interferon, differ from those for IFN-λ3, but both IFN-λ and IFN-α activate the same intracellular pathway (Jak/STAT), which results in expression of many interferon stimulated genes.[4–6]

SNPs rs12979860 and rs8099917, respectively located 3 and 8 kb upstream of IL28B, were the variants most strongly associated with treatment response in these studies. Among treatment naive G1-infected subjects of European ancestry who were enrolled in the IDEAL study, approximately 69% of those who carried 2 C alleles (C/C) at rs12979860 achieved an SVR compared with 33% of those with the C/T genotype and 27% with genotype T/T.[7] Consistent findings were reported for rs8099917 among Japanese, Australian, and European populations.[2–3] These studies demonstrated that carriage of 2 IL28B favorable alleles strongly, but not fully, predicted SVR, while carriage of 1 or 2 unfavorable alleles did not completely predict failure to respond to treatment. It appears that rs12979860 is more predictive of SVR than rs8099917, especially among people of African ancestry in whom rs8099917 is less polymorphic than rs12979860.[1]

In the current issue of Clinical Gastroenterology and Hepatology, Stättermayer and colleagues performed IL28B genotype testing for rs12979860 and rs8099917 in 682 Austrian subjects (G1 = 372; G2/3 = 208; G4 = 102) who completed treatment with peginterferon and ribavirin and agreed to return for genetic testing.8 They found that subjects infected with G1/4 who carried 2 C alleles at rs12979860 (ie, the most favorable genotype) had a greater decline in HCV ribonucleic acid (RNA) 24 hours after the first injection of interferon than did G1/4-infected subjects who carried a T allele (either C/T or T/T). Similarly, subjects infected with G1/4 who carried rs12979860 C/C were more likely to achieve a rapid virological response (RVR; G1: 38% vs 12%) and SVR (G1: 79% vs 43%) as compared with carriers of the T allele. Among subjects infected with G2/3, rs12979860 C/C carriers had a higher likelihood of RVR (75% vs 53%), but the difference for SVR (81% vs 72%) did not reach statistical significance. IL28B rs12979860 genotype was the strongest pretreatment predictor of SVR, but when the initial response to peginterferon and ribavirin was considered, RVR rather than IL28B genotype was the strongest predictor of SVR in this population. The authors concluded that IL28B genotype influenced the rate of initial viral decline with peginterferon/ribavirin treatment and that IL28B genotype, in conjunction with RVR, might be useful parameters in predicting SVR in G1/4 subjects.

The findings of Stättermayer and coworkers confirm prior reports of IL28B genotype testing among subjects treated with peginterferon + ribavirin. Several investigators have reported that subjects with rs12979860 C/C have a greater initial decline in HCV RNA level and a higher likelihood of achieving RVR and SVR.[1,7,9] Thompson reported that IL28B genotype is the most important pretreatment variable to predict SVR, but IL28B genotype loses importance as a predictor of SVR when RVR is included in a multivariate analysis.[7] Stättermayer confirmed that rs12979860 is more informative than rs8099917 as a pretreatment predictor of SVR among those of European ancestry.[1] In total, studies from Stättermayer and others show a strong association of IL28B genotype with virological response to peginterferon + ribavirin treatment, including the rate of early viral decline and the likelihood of achieving RVR and SVR.

The human genome project promised to introduce an era of personalized medicine, in which genetic testing would be used to predict the likelihood of clinical outcomes, including response to drugs, in individual patients.[10] In 2010 several clinical laboratories announced assays for IL28B rs12979860 genotype. Gastroenterologists now must decide whether to obtain IL28B genotype for their HCV-infected patients and, if so, how to incorporate these results into decisions regarding hepatitis C treatment. IL28B genotype joins a considerable list of pretreatment factors that have been shown to predict the probability of SVR, including HCV genotype, HCV RNA level, severity of liver fibrosis, and racial ancestry. Information on each of these factors can help inform the physician and patient of the likelihood of achieving an SVR, however, none alone is sufficient to guarantee or preclude the possibility of achieving an SVR. Although IL28B genotype alone is insufficient for deciding whether or not a patient is likely to respond to peginterferon and ribavirin, we believe that mathematical clinical prediction models based on IL28B genotype and clinical characteristics may prove useful for predicting SVR. Indeed, among interferon nonresponders who were re-treated with peginterferon + ribavirin in the HALT-C Trial, we have presented "proof of concept" that a model that includes IL28B plus some commonly measured clinical variables (HCV viral load, liver fibrosis score and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio) has good discrimination and predictive ability for the probability of SVR (O'Brien et al, Hepatology 2010;52:382A [abstract]). If validated, such a model could be used to calculate individually tailored probabilities of achieving an SVR for patients. Clinical prediction models may also be useful for ontreatment predictions of SVR.

The availability of IL28B genotype testing to help predict SVR coincides with another major advance in the treatment of chronic hepatitis C, the introduction of direct-acting antiviral agents (DAAs) that specifically target enzymes critical to HCV replication. At this writing, it appears likely that 2 HCV-specific protease inhibitors, boceprevir and telaprevir, will be approved by the Food and Drug Administration (FDA) in 2011. Data from clinical trials suggest that adding a protease inhibitor to the peginterferon + ribavirin regimen increases the overall SVR rate among treatment naive G1-infected patients to 65%–75% (Bacon et al, Hepatology 2010;52:216 [abstract]; Jacobson et al, Hepatology 2010;52:211 [abstract]). However, adding a viral protease inhibitor to current standard of care is not without additional risks. Patients taking these agents are subject to several potential adverse effects, including anemia and skin rash. Furthermore, patients who fail to achieve SVR on a regimen that includes a protease inhibitor will likely harbor resistant viruses that limit future use of protease inhibitors in that patient. Initial studies suggest that IL28B genotype may be predictive of response to treatment with protease inhibitors, too. Among Japanese patients who received telaprevir + peginterferon + ribavirin, Akuta and colleagues reported an SVR rate of 83% for subjects carrying rs12979860 C/C as compared with 32% among subjects who carried a T allele.[11] If confirmed in other populations, these data suggest that carriers of the less favorable IL28B genotypes will be less likely to respond to triple therapy that includes protease inhibitors and raise the possibility that IL28B genotype-based models may be useful for predicting the likelihood of SVR in response to treatment with peginterferon + ribavirin + protease inhibitors.

Until now, the outcome of treatment for chronic hepatitis C could be broadly classified as either successful (SVR) or futile (nonresponse). The advent of the direct-acting antiviral agent (DAA) era promises to increase the number of patients for whom treatment is successful, but also introduce a third outcome— patients who not only fail treatment, but also harbor resistant viral strains that may compromise future treatment options. Thoughtful incorporation of IL28B genotyping into treatment decision-making may serve to increase the number of patients for whom treatment is successful while minimizing those in whom it is deleterious.

References

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

2.Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009;41:1100–1104.

3.Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009;41:1105–1109.

4.O'Brien TR. Interferon-alfa, interferon-lambda and hepatitis C. Nat Genet 2009;41:1048–1050.

5.Kotenko SV, Gallagher G, Baurin VV, et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol 2003;4:69–77.

6.Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol 2003;4:63–68.

7.Thompson AJ, Muir AJ, Sulkowski MS, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 2010;139:120–129, e18.

8.Stättermayer A, Stauber R, Hofer H, et al. Impact of IL28B genotype on the early and sustained virologic response in treatment-naïve patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2011;9:344–350.

9.McCarthy JJ, Li JH, Thompson A, et al. Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin. Gastroenterology 2010;138:2307–2314.

10.Feero WG, Guttmacher AE, Collins FS. Genomic medicine–an updated primer. N Engl J Med 2010;362:2001–2011.

11.Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatol 2010;52:421–429.

Source
A Multicenter Study

C. Puoti; G. Barbarini; A. Picardi; M. Romano; A. Pellicelli; A. Barlattani; F. Mecenate; R. Guarisco; O. M. Costanza; L. Spilabotti; L. Bellis; M. E. Bonaventura; O. Dell' Unto; M. G. Elmo; A. M. Nicolini; L. Nosotti; and F. Soccorsi

Posted: 07/05/2011; J Viral Hepat. 2011;18(6):393-399. © 2011 Blackwell Publishing

Abstract and Introduction

Abstract

Rapid virological response (RVR) is now considered the strongest predictor of sustained virological response (SVR) in patients with HCV undergoing antiviral treatment, and thus, shorter antiviral treatment for these patients has been suggested. However, no data exist on the predictive value of RVR in HCV carriers with normal ALT values. A total of 137 patients with persistently normal ALT treated with peginterferon alfa 2a and ribavirin were studied. Fifteen patients dropped out early because of side effects, and in 10 patients with HCV-1 treatment was discontinued because of lack of early virological response (EVR). RVR was observed in 68% of the patients (42% patients with HCV-1, 90% HCV-2 and 64% HCV-3). An end-of-treatment response was observed in 86% of the patients (68% HCV-1, 100% HCV-2 and 91% HCV-3). SVR was maintained in 91 patients (46% HCV-1, 97% HCV-2 and 82% HCV-3). Overall, 92% patients with rapid response did obtain HCV eradication vs only 38% of those without rapid response. HCV-1 patients with baseline HCV RNA <400 × 103 IU/mL were more likely to achieve RVR and SVR than those with higher HCV RNA levels. We conclude that patients with genotype 1 and normal ALT who achieve HCV RNA negativity at week 4 may have a higher probability of eradicating their infection. Because of the concomitant favourable demographic and virological features often found in this particular subset of patients, the duration of therapy in these people might be shortened in the case of RVR. Persistently normal alanine aminotransferase levels patients with genotype 2 or 3 have a high chance of achieving SVR, so retesting of HCV RNA during treatment may have no additional practical value in these subjects.

Introduction

Historically, patients with chronic hepatitis C virus (HCV) infection and persistently normal alanine aminotransferase levels (PNALT) have been classified as 'healthy' or 'asymptomatic',[1–3] not thought to progress and thus excluded from antiviral treatment.[4,5] Thus, whether patients with chronic hepatitis C (CHC) and normal ALT should be offered antiviral treatment in clinical practice has been disputed until recently.[6–8] Interferon (IFN) treatment is associated with important side effects and is rather expensive, whereas the risk of progression of the disease in this setting is extremely low.[9–11] For these reasons, the first Consensus Conferences on HCV discouraged treatment in subjects outside clinical trials.[4,5] The introduction of the combination of peginterferon (PEG-IFN) plus ribavirin (RBV) resulted in higher response rates.[8–11] The first multicentric study[12] demonstrated the efficacy and safety of therapy with PEG-IFN a-2a plus RBV also in patients with PNALT; however, in this study, subjects with HCV-1 were treated with a fixed RBV dose lower than that universally recommended for this subset of patients (800 mg/day instead of 1000–1200 mg/day). Simulation studies suggest that sustained virological response (SVR) in HCV-1 patients with PNALT significantly increases when the standard weight-adjusted dose of RBV is administered.[13] More recently, an Italian multicentric study showed higher efficacy of the approved dosage of RBV (1000–1200 mg/day) in patients with HCV-1 and PNALT and excellent sustained responses in those with HCV-2 or 3 infection.[14]

Given the side effects and costs of antiviral therapy, the optimal duration of treatment, and the possibility of treating patients for shorter periods has been evaluated.[15–18] According to the new concept of 'response-guided therapy' (RGT), tailored duration of antiviral therapy with shorter treatment for patients with rapid virological response (RVR) has been suggested, chiefly for patients with HCV-1.[19] Despite several studies on the predictive value of RVR in HCV patients with abnormal ALT levels, no data thus far exist on its predictability of response in patients with persistently normal ALT levels. Thus, we have decided to conduct this multicentric study to assess whether RVR might be predictive of SVR also in this particular subset of patients with HCV and to evaluate the cost effectiveness to determine HCV RNA at 4 weeks in these 'easy-to-treat' subjects.

Patients and Methods

Eligibility and Definition

Hepatitis C virus carriers were defined as having HCV RNA positivity by polymerase chain reaction (PCR) and normal ALT in at least four different occasions 3 months apart over a 12-month period. Exclusion criteria were age <18 years or >70 years, HBsAg or human immunodeficiency virus positivity, previous IFN treatment, serum HCV RNA negativity, history of heavy alcohol abuse, clinical or ultrasound (US) signs of cirrhosis, hepatocellular carcinoma, abnormal ferritin levels, neutropaenia (absolute neutrophil count <1500 cells/mm3), thrombocytopaenia (<100 000 platelets/mm3), anaemia (haemoglobin concentration <12 g/dL in women and <13 g/dL in men) and any abnormality of other liver function tests or routine biochemical tests. Pregnant or lactating women were also excluded. All fertile men and women who participated in the trial were strongly advised to use effective contraception methods during treatment and for 6 months after the end of treatment. All patients reporting contraindications to IFN or RBV treatment and those suffering from significant coexisting medical conditions were excluded from this study. Scarce motivation or refusal to sign informed written consent to treatment was considered exclusion criteria.

Serum Virological and Biochemical Assays

Antibodies to HCV were tested by the ELISA III (Ortho Diagnostic System, Raritan, NJ, USA). HCV RNA quantification was obtained using a PCR-based commercially available test (Cobas Amplicor HCV Monitor v 2.0; Roche Molecular Systems, Basel, Switzerland). HCV genotyping was performed using a commercial kit (INNO-LiPA HCV II; Innogenetics, Ghent, Belgium). Aminotransferases and other serum liver function tests were determined by routine methods in the local laboratory. The upper limit of normal (ULN) ALT value was 40 IU/L.

Liver Histology

Liver biopsy specimens obtained within 6 months before study onset were evaluated using the Metavir classification.[20] Ultrasound-guided liver biopsy was performed using a modified Menghini needle. Formalin-fixed, paraffin-embedded specimens were routinely stained with haematoxylin–eosin and reviewed by local pathologists blinded to clinical and biochemical data.

Liver Stiffness Assessment

Liver stiffness (LS) was evaluated by transient elastography (Fibroscan®, Echosens SA, Paris, France). LS was assessed on the right lobe of the liver, through the intercostal spaces, with the patient in the supine position and the right arm in maximal abduction. Ten validated measures were performed in each patient. The success rate was calculated as the number of validated measures divided by the total number of measures. Results were expressed in kilopascals (kPa). The median value was considered representative of the hepatic stiffness. Only procedures with 10 validated measures and a success rate of at least 60% were considered reliable.

Study Design

All patients received PEG-IFN α-2a 180 μg once weekly plus RBV 800 mg/day for 24 weeks (patients with HCV-2 and HCV-3) or 1000–1200 mg/day for 48 weeks (patients with HCV-1, according to body weight). Stepwise reductions of the dosage of IFN and of RBV were permitted in patients experiencing clinically significant adverse events. The dosage of RBV was reduced in patients showing a decrease in the haemoglobin concentration to <10 g/dL, and treatment was discontinued if the haemoglobin concentrations decreased to <8.5 g/dL despite 4 weeks of treatment with a reduced dosage of the drug. Given the aims of this study, PEG-IFN monotherapy was not allowed. Serum HCV RNA concentration was determined at weeks 4, 12 and 24 in patients infected by genotypes 2 and 3 and at weeks 4, 12, 24, 36 and 48 in patients infected by genotype 1. HCV RNA was further evaluated in all patients 24 weeks after the end of the treatment.

Definition of Virological Responses

Rapid virological response (RVR) was defined as undetectable serum HCV RNA at week 4 of treatment. Early virological response (EVR) was defined as detectable serum HCV RNA at week 4 and either undetectable HCV RNA or >2 log10 decrease in serum HCV RNA level at week 12. End-of-treatment response (EoTR) was defined as the absence of detectable HCV RNA at the end of the treatment, while SVR was defined as the absence of detectable HCV RNA levels at end of the follow-up (24 weeks after the end of the treatment). Relapse (REL) was defined as the reappearance of HCV RNA during the follow-up in subjects with previous EoTR.[21]

Statistical Analysis

Statistical significance was assessed by the Chi-squared test with Yates' and Bonferroni's correction and 95% confidence intervals, analysis of variance (ANOVA) and Student's t-test for independent samples. Logistic regression and analysis of covariance were used to analyse categorical and continuous variables, respectively. A P-value of <0.05 was considered significant. Data are expressed as means ± SD.

Results

One hundred and thirty-seven consecutive patients (102 women, range 19–64 years) referred because of HCV positivity and PNALT to the Liver Units participating in this study were evaluated (see appendix). Fifty-eight of one hundred and thirty-seven patients (42%) had HCV-1, 67 had HCV-2 (49%) and 12 (9%) had HCV-3. The mean serum HCV RNA level was 220 ± 95 × 103 IU/mL (range 1.9–4.800 × 103 IU/mL). Only 35% of the 137 patients in study had a history of previous exposure to blood (transfusion, 16; previous intravenous drug addiction (IVDA), 11; unsafe sex with multiple partners, 4; occupational exposure, 6; unsafe tattooing or piercing, 11). In the other patients, discovery of HCV positivity occurred recently by chance as a result of blood donations, screening for endoscopic or surgical procedures, hospitalizations and screening of relatives of HCV-positive patients. In these patients, the actual duration of HCV infection cannot be evaluated. No differences in demographical, virological and histological features were seen between these patients and those with known risk factors for blood exposure.

Liver histology was available in 115/137 patients: 22 patients (19%) had normal liver, 89 (77%) showed F1 fibrosis, three had F2 fibrosis and one had F3 fibrosis. In the remaining 22 patients, histological data were not available because of refusal to perform biopsy (14 patients) or because of inadequate specimens (eight patients). These patients were offered transient elastography through Fibroscan® before treatment, showing normal or low values of LS in 14/22 patients (mean 3.2 ± 2.0 kPa, range 3.0–6.1 kPa), indicative of F0–F1 fibrosis; six patients had LS indicative of F2 fibrosis (mean 8.2 ± 3.4 kPa, range 7–12 kPa), whereas the latter two patients had higher values of stiffness (13.2 and 14.0 kPa, respectively). No demographical differences were seen between these patients and those undergoing liver biopsy. The main demographical, histological and virological features of the patients are shown in Table 1.

Fifteen patients (8 HCV-1, 6 HCV-2, 1 HCV-3) early dropped out because of side effects or refuse to continue treatment: severe pyrexia (one patient), depression (one patient), refuse to continue treatment (two patients), fatigue and other constitutional symptoms (four patients), private problems (three patients), failed to return (four patients). The mean duration of treatment in this group was 3 weeks (range 1–5 weeks). In these subjects, RVR was not evaluated.

The remaining 122 patients (50 HCV-1, 61 HCV-2, 11 HCV-3) did continue treatment (Fig. 1). RVR was seen in 83/122 patients (68%): 21/50 patients with HCV-1 (42%), 55/61 HCV-2 (90%) and 7/11 (64%) HCV-3 (χ2 = 29.416, P ≤ 0.0001) (Table 2). Ten out of the 50 patients harbouring HCV type 1 (20%) showed persistent HCV RNA positivity at 12 weeks (HCV RNA drop ≤2 log10 decrease); thus in these subjects, treatment was discontinued, according to the stopping rule policy for patients with HCV-1 (absence of EVR) (Figs 1 & 2).


Figure 1.
Overall rates of Rapid virological response (RVR) and sustained virological response (SVR) in the patients in study.


Figure 2.
Rates of sustained virological response (SVR) according to presence or absence of Rapid virological response (RVR) in patients with HCV-1.

End-of-treatment response was seen in 105/122 patients (86%): 34/50 of patients with HCV-1 (68%, 21 with RVR and 14 without RVR), all of those harbouring HCV-2 and 10/11 (91%, seven with RVR and three without RVR) of HCV-3 infected subjects were HCV RNA negative at the end of the antiviral treatment (Table 2).

Virological response at the month 6 of follow-up (SVR) was maintained in 91/122 patients (75%): 23/50 patients with HCV-1 (46%), 59/61 patients with HCV-2 (97%) and 9/11 (82%) patients with HCV-3 (χ2 = 24.397, P = 0.0001) (Table 2). Thus, REL after achieving EoTR was seen in 32% of patients with HCV-1 (11/34), 3% of HCV 2 (2/61) and 10% of HCV-3 (1/10: χ2 = 16.077, P < 0.0001).

Seventy-six of eighty-three (92%) subjects with RVR (Fig. 1) did obtain SVR vs only 38% of those without RVR (15/39; P < 0.0001). By stratifying SVR rates by genotype and RVR, we found that among patients with HCV-1 SVR was observed in 16/21 (76%) of subjects with RVR and only 7/29 (24%) of those without RVR (χ2 = 4.812, P < 0.02; Fig. 2); in patients with HCV-2, a SVR was achieved in 54/55 patients (98%) with RVR and 5/6 (83%) of those without RVR (χ2 = 0.536, P = 0.46, N.S.; Fig. 3), and in patients with HCV-3, SVR was found in 6/7 (86%) of subjects with RVR and 3/4 (75%) of those without RVR (χ2 = 0.136, P = 0.71, N.S.; Fig. 4).


Figure 3.
Rates of sustained virological response (SVR) according to presence or absence of Rapid virological response (RVR) in patients with HCV-2.


Figure 4.
Rates of sustained virological response (SVR) according to presence or absence of Rapid virological response (RVR) in patients with HCV-3.

HCV-1 patients with baseline HCV RNA <400 × 103 IU/mL were more likely to achieve RVR and SVR. Among the 40 patients with HCV 1 who had the full treatment course, 22 (55%) had HCV RNA <400 × 103 IU/mL and 18/40 had HCV RNA >400 × 103 IU/mL. RVR was seen in 16/22 of the former (73%) and only 5/18 of the latter (28%; χ2 = 6.320, P = 0.012), although continuation of the treatment did allow SVR in 13/16 (81%) and 3/5 (60%) of the patients, respectively (N.S.) (Table 3).

Forty-four of one hundred and twenty-two patients (36%) had ALT levels below 50% of the ULN (≤20 U/L) and 78 patients had ALT ≥ 20 U/L. However, we found that baseline ALT levels did not influence the rates of RVR and SVR, as no differences were seen between the two groups of patients. Logistic regression analysis was applied to identify predictors of SVR. Factors significantly associated (P < 0.05) with SVR on univariate analysis were lower baseline viral load (<400 × 103 IU/mL), non-1 genotype, female gender, lower BMI (<25 kg/m2) and HCV RNA undetectable at week 4 of treatment. At multivariate analysis, only RVR and non-1 genotype were predictors of SVR.

Safety of the treatment was excellent. Except for the 15 patients in which severe adverse events requiring very early treatment premature withdrawal were seen, in the others 122 subjects who did continue treatment no major side effects were reported. In particular, the appearance of anaemia was observed in 21 out of these 122 patients, but reduction of RBV according to the protocol study was needed in only six patients, three of which failed to have SVR. No signs or symptoms of severe thyroid dysfunction were seen.

In all these 122 subjects, side effects were very mild in severity and not different from those seen among patients with abnormal ALT treated with the same schedules during the same period. The more frequently reported events were mild asthenia, minor depression or irritability, fever following early IFN administrations.

Discussion

It is known that HCV carriers with persistently normal ALT levels overall show demographic and virological features (prevalence of women and non-1 HCV genotypes, younger age, often lean, mild liver damage or even absence of fibrosis) traditionally associated with higher response rates to combined treatment with PEG-IFN plus RBV,[2,22–24] and thus, they might achieve SVR even with shorter than usually recommended treatment periods.[25] Despite several studies have evaluated the ability of RVR to predict SVR in HCV patients with elevated ALT levels,[15–18] no data exist on this topic in subjects with PNALT. Furthermore, previous studies have shown that HCV subjects with PNALT have similar[12,13] or even higher[14] chances of SVR than those with abnormal ALT values, and thus, the identification of early parameters able to predict sustained HCV eradication in this setting is needed to avoid unnecessary prolongation of therapy in this population of 'super-responders'. The main predictive factor up till now identified is represented by the absence of HCV RNA at week 4 of treatment, the so-called RVR.

It has been shown that patients with chronic hepatitis C and persistently normal ALT have similar viral kinetics as those with elevated ALT levels during antiviral therapy.[26]

Recently, it has been reported that a 2 log drop in HCV RNA at day 28 was the best predictor of SVR in patients with HCV-1 infection and PNALT treated with PEG-IFN alpha 2 b plus RBV[27] and that a failure to reduce viral load by 2 logs correctly identified patients with a low (<15%) probability of achieving a SVR.

Our data clearly show that patients with PNALT and HCV RNA negativity after 4 weeks of treatment have higher probability to eradicate their HCV infection than those without RVR and that even HCV-1 patients with RVR have excellent rates of SVR: analysing the rates of SVR by genotype distribution, we found that among patients with RVR, an SVR was achieved in 76% of patients with HCV-1, 98% of HCV-2 and 86% of HCV-3. By contrast, in the absence of RVR, an SVR was observed in 7/29 (24%), 5/6 (83%) and 3/4 (75%) of the three groups of patients, respectively.

Thus, the presence or absence of RVR might have great clinical relevance mainly in patients with HCV-1 type. Indeed, whilst patients with HCV-2 or HCV-3 showed good SVR rates regardless of the presence of RVR, in those with HCV-1 genotype the probability to reach SVR significantly decreased from 76% in patients with RVR to 24% in those without RVR. It means that a 4-week stopping rule policy based on RVR does not seem to be cost effective in patients with PNALT and non-1 genotypes, given the exceedingly high virological responses in this group; by contrast, it could have important consequences for the practical management of HCV-1 patients with normal ALT. In fact, patients infected with HCV genotype 1 who became HCV RNA negative by week 4 were more likely to achieve SVR than those who did not become HCV RNA negative until week 12. However, persistent HCV RNA positivity at week 4 does not justify early stopping of the treatment, as 7 HCV-1 patients without RVR did finally achieve SVR.

Recent data suggest that a baseline level of 400 × 103 IU/mL is the most effective cut-off for a high or low probability to achieve SVR in genotype 1-infected patients.[19] Our findings confirm that low baseline HCV RNA values might influence the probability of reaching SVR in patients with HCV-1: in our series of patients, SVR was seen in 81% of HCV-1 patients with RVR and HCV RNA levels <400 × 103 IU/mL vs 60% of those with RVR but HCV RNA levels >400 × 103 IU/mL, although this trend was not significant. It has been shown that HCV-1 patients with abnormal ALT levels and with low baseline HCV RNA level (<400 × 103 IU/mL) and a RVR, there was no significant difference between 24 and 48 weeks of PEG-IFN plus RBV administration, thus suggesting that 24 weeks of therapy is the appropriate treatment duration in this group.[28] By contrast, ALT baseline levels did not influence the rates of RVR and SVR, according to previous studies[12,14] Recently, it has been demonstrated that HCV-1 patients with low baseline HCV RNA levels (<600 000 IU/mL) and an RVR achieve an SVR rate of up to 90.%[18] Jensen et al.[29] reported that up to 23% of HCV-1 patients treated with PEG-IFN plus RBV achieved RVR, 89% of these reaching SVR after treatment duration of 24 weeks.

The higher than usually SVR rates found in our study in patients with genotype 1 might be explained by several factors, such as the high prevalence of women, the mild degree of liver damage, the relatively low mean age and, last but not the least, the normal BMI values observed in the majority of the patients.

In summary, this is the first study showing that patients with genotype 1 and normal ALT reaching HCV RNA negativity at week 4 might have excellent probability to eradicate their infection. Because of the concomitant favourable demographic and virological features often found in this particular subset of patients, the duration of therapy in patients with PNALT might be shortened in the case of RVR. By contrast, PNALT patients with genotype 2 or 3 in any case have a high chance of achieving SVR, so retesting of HCV RNA during treatment has no practical value in these subjects.[30]

References

1.Puoti C. HCV carriers with persistently normal aminotransferase levels: normal does not always mean healthy. J Hepatol 2003; 38: 529–532.

2.Zeuzem S, Alberti A, Rosenberg W et al. Management of patients with chronic hepatitis C virus infection and _normal' aminotransferase activity. Aliment Pharmacol Ther 2006; 24: 1133–1149.

3.Puoti C, Magrini A, Stati T et al. Clinical, histological, and virological features of hepatitis C virus carriers with persistently normal or abnormal alanine transaminase levels. Hepatology 1997; 26: 1393–1398.

4.Marcellin P, Levy S, Erlinger S. Therapy of Hepatitis C: patients with normal aminotransferase levels. National Institutes of Health Consensus Development Conference Panel Statement: management of hepatitis C. Hepatology 1997; 26(Suppl.1): 133S–136S.

5.Tassopoulos NC. Treatment in patients with normal ALT levels. EASL international consensus conference on hepatitis c: consensus statement. J Hepatol 1999; 30: 956–961.

6.Puoti C, Castellacci R, Montagnese F et al. Histological and virological features and follow up of hepatitis C virus carriers with normal aminotransferase levels: the Italian prospective study of the asymptomatic C carriers [ISACC]. J Hepatol 2002; 37: 117–123.

7.Pradat P, Alberti A, Poynard T et al. Predictive value of ALT levels for histologic findings in chronic hepatitis C: a European collaborative study. Hepatology 2002; 36: 973–977.

8.Puoti C, Guido M, Mangia A, Persico M, Prati D. Clinical management of HCV carriers with normal aminotransferase levels. Dig Liver Dis 2003; 35: 362–369.

9.Bacon BR. Treatment of patients with hepatitis c and normal serum aminotransferase levels. Proceedings of the NIH consensus conference management of hepatitis C. Hepatology 2002; 36(Suppl. 1): S179–S184.

10.Strader DB, Wright T, Thomas DL, Seef LB. Diagnosis, management and treatment of hepatitis C. AASLD Practice Guideline. Hepatology 2004; 39: 1147–1171.

11.Dienstag JL, McHutchison JG. American Gastroenterological Association [AGA] Medical Position Statement on the Management of Hepatitis C. Gastroenterology 2006; 130: 225–264.

12.Zeuzem S, Diago M, Gane E et al. Peginterferon alfa-2a [40KD] and ribavirin in patients with chronic hepatitis C and normal aminotransferase levels. Gastroenterology 2004; 127: 1724–1732.

13.Snoeck E, Hadziyannis SJ, Puoti C et al. Predicting efficacy and safety outcomes in patients with hepatitis C virus genotype 1 and persistently 'normal' alanine aminotransferase levels treated with peginterferon alfa-2a (40KD) plus ribavirin. Liver Int 2008; 28: 61–71.

14.Puoti C, Pellicelli AM, Romano M et al. Treatment of HCV carriers with persistently normal alanine aminotransferase levels with peginterferon alfa-2a and ribavirin: a multicentric study. Liver Int 2009; 29: 1479–1484.

15.Mangia A, Andriulli A. Tailoring the length of antiviral treatment for hepatitis C. Gut 2010; 59: 1–5.

16.Zeuzem S, Hultcrantz R, Bourliere M et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004; 40: 993–999.

17.Shiffman M, Suter F, Bacon BR et al. for the ACCELERATE Investigators. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3. N Engl J Med 2007; 357: 124–134.

18.Zeuzem S, Buti M, Ferenci P et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006; 44: 97–103.

19.Zeuzem S, Berg T, Moeller B et al. Expert opinion on the treatment of chronic hepatitis C. J Viral Hepat 2009; 16: 75–90.

20.The French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 1994; 20: 15–20.

21.Ghany MG, Strader DB, Thomas DL, Seef LB. Diagnosis, management and treatment of hepatitis C. Hepatology 2009; 49: 1335–1374.

22.Puoti C, Castellacci R, Montagnese F. Hepatitis C virus carriers with normal aminotransferase levels: healthy people or true patients? Dig Liver Dis 2000; 32: 634–643.

23.Puoti C, Bellis L, Martellino F et al. Chronic hepatitis C and 'normal' ALT levels: treat the disease not the test. J Hepatol 2005; 43: 534–535.

24.Puoti C, Bellis L, Galossi A et al. Antiviral Treatment of HCV carriers with normal ALT. Mini Rev Med Chem 2008; 8: 150–152.

25.Alberti A. Towards a more individualised management of HCV patients with initially or persistently normal alanine aminotransferase levels. J Hepatol 2005; 42: 266–274.

26.Kronenberger B, Herrmann E, Micol F, von Wagner M, Zeuzem S. Viral kinetics during antiviral therapy in patients with chronic hepatitis C and persistently normal ALT levels. Hepatology 2004; 40: 1442–1449.

27.Deltenre P, Canva V, El Nady M et al. A 2-log drop in viral load at 1 month is the best predictor of sustained response in HCV patients with normal ALT: a kinetic prospective study. J Viral Hepat 2009; 16: 500–505.

28.Moreno C, Deltenre P, Pawlotsky JP, Henrion J, Adler M, Mathurin P. Shortened treatment duration in treatmentnaive genotype 1 HCV patients with rapid virological response: a meta-analysis. J Hepatol 2010; 52: 25–31.

29.Jensen DM, Morgan TR, Marcellin P et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006; 43: 954–960.

30.Puoti C, Bellis L, Guarisco R, Dell'Unto O, Spilabotti L, Mitidieri Costanza O. HCV carriers with normal alanine aminotransferase levels: healthy persons or severely ill patients? Dealing with an everyday clinical problem. Eur J Intern Med 2010; 21: 57–61.

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J Viral Hepat. 2011 Jul;18(7):e232-e241. doi: 10.1111/j.1365-2893.2011.01440.x. Epub 2011 Feb 17.

Thein HH, Walter SR, Gidding HF, Amin J, Law MG, George J, Dore GJ.

National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Sydney, NSW, Australia Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada Toronto Health Economics and Technology Assessment Collaborative (THETA), Toronto, ON, Canada Storr Liver Unit, Westmead Hospital and Westmead Millennium Institute, University of Sydney, Sydney, NSW, Australia HIV/Immunology/Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, NSW, Australia.

Abstract

Summary.  Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the major risk factors for hepatocellular carcinoma (HCC). We examined trends in the incidence of HCC among a population-based cohort of people infected with HBV or HCV. HBV and HCV cases notified to the New South Wales Health Department between 1992 and 2007 were linked to the Central Cancer Registry, Registry of Births, Deaths and Marriages, and National HIV/AIDS Registries. Crude HCC incidence rates were estimated using person-time methodology. Age-standardized incidence rates were calculated using the 2001 Australian population. Trends in incidence were examined using join point regression models. Between 1992 and 2007, 1201 people had a linked HCC record: 556 of those with HBV; 592 with HCV; 45 with HBV/HCV co-infection; and 8 with HIV co-infection. The overall age-standardized HCC incidence rates declined non-significantly from 148.0 (95% confidence intervals (CI) 63.7, 287.4) per 100 000 population in 1995 to 101.2 (95% CI 67.3, 144.6) in 2007 among the HBV monoinfected group and significantly from 151.8 (95% CI 62.4, 299.8) per 100 000 population to 75.3 (95% CI 50.8, 105.5) among the HCV monoinfected group. However, incidence rates in the HCV monoinfected group progressively increased from the period 1992-1997 to 2004-2007 when adjusted for age, sex, and birth cohort, and the total number of cases per annum continued to increase. Despite declines in the age-adjusted incidence rates of HCC over time, the absolute number of cases increased likely due to the ageing cohort and an increasing prevalence of both hepatitis B and C in Australia.

© 2011 Blackwell Publishing Ltd.

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Hepatology June 2011

Jeremie Guedj and Alan S. Perelson

From Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM.

"we estimated that telaprevir induced a four-fold more rapid second-phase viral decline than IFN-based therapy.....Even if resistance was avoided by using an appropriate combination of DAAs, other factors might affect our prediction. First, the ability of IFN-sparing antiviral strategies to reach every viral population residing in the liver or in extrahepatic reservoirs is unknown. Second, the combination of several DAAs might increase toxicity and thus the adherence to treatment. How this may impact treatment duration has only been touched on in this study, and more data are needed to understand how the lack of adherence to treatment may favor the appearance and persistence of resistant virus.

Thus, attainment of SVR in less than 10 weeks in 95% of fully compliant patients would require combination drug regimens (1) that have a genetic barrier high enough so that resistance is avoided, (2) that have high drug penetration into all anatomical sites that contain infected cells, and (3) for which the pharmacokinetics of the drugs in the regimen allow the effectiveness of the regimen against viral production to be maintained at high levels throughout the course of treatment.

In summary, our finding that the second-phase slope increases with the effectiveness of therapy and our expectation that a combination of DAA agents will suppress the growth of drug-resistant variants holds open the promise that more effective therapies that use combinations of DAA agents may, one day, lead to SVR with treatment durations of 2-3 months."

ABSTRACT

Hepatitis C virus (HCV) RNA decay during antiviral therapy is characterized by a rapid first phase, followed by a slower second phase. The current understanding of viral kinetics attributes the magnitude of the first phase of decay to treatment effectiveness, whereas the second phase of decay is attributed to the progressive loss of infected cells. Here, we analyzed data from 44 patients treated with telaprevir, a potent HCV protease inhibitor. Using a viral kinetic model that accounts for the pharmacokinetics of telaprevir, we found the second-phase slope of viral decline to be strongly correlated with treatment effectiveness and to be roughly four-fold more rapid than has been reported with interferon-based therapies. Because telaprevir is not known to increase the death rate of infected cells, our results suggest that the second-phase slope of viral decline is driven not only by the death of infected cells, but may also involve other mechanisms, such as a treatment-effectiveness-dependent degradation of intracellular viral RNA. As a result of the enhanced viral decay caused by the high antiviral effectiveness of telaprevir, we predict that if drug resistance could be avoided by using an appropriate combination of antiviral agents, treatment duration needed to clear HCV might be dramatically shortened. Indeed, we predict that in 95% of fully compliant patients, the last virus particle should be eliminated by week 7 of therapy. If the remaining infected hepatocytes act as a potential reservoir for the renewal of infection, no more than 10 weeks of treatment should be sufficient to clear the infection in 95% of fully compliant patients. However, if patients miss doses, treatment duration would need to be extended.

Chronic hepatitis C virus (HCV) infection has a worldwide prevalence of approximately 3%.1 Achieving a long-term, sustained virologic response (SVR), defined as undetectable HCV RNA in serum 24 weeks after the end of treatment, is the most effective way to prevent disease progression. Currently, treatment outcome with pegylated interferon (PEG-IFN) and ribavirin (RBV) is correlated with HCV genotype, and SVR is only achieved in approximately 50% of patients infected with genotype 1 HCV.

After the initiation of high doses of daily IFN with or without RBV, viral kinetics are characterized in most patients by a biphasic decline, where a rapid initial decline lasting for 1-2 days is followed by a slower, but sustained, second phase of viral decay (Fig. 1), where HCV RNA declines 0.42 log10 IU/mL/week, on average, with high variation among patients (standard deviation, 0.36 log10 IU/mL/week).2, 3 Mathematical modeling of viral kinetics has provided valuable insights for the understanding of the determinants of HCV RNA decay after treatment initiation.4 In particular, it has been proposed that the second phase of viral decline is due to the loss of infected cells, and thus, the high variability in the second phase of viral decline could reflect the variability in the strength of the immune response.2 Although several observations support the possibility that the immune response is involved in the second phase of viral decline,2, 5 no means exists to directly quantify the loss rate of infected cells in vivo, and the predictions made by mathematical modeling remain to be validated. Whatever the mechanisms involved in the second phase of viral decline, its determination is of great interest, because it can ultimately determine the length of time of treatment that needs to be given before all virus and infected cells are expected to be cleared.3

Direct-acting antivirals (DAAs) constitute a new stage in HCV therapy. These drugs inhibit specific HCV enzymes important for viral replication, such as the NS3 protease, and thus allow for a more profound antiviral effect than the current IFN-based therapy. Similar to what was observed with IFN-based therapy, HCV RNA after the initiation of protease-inhibitor therapy was found to decline in a biphasic manner, with, in most patients, a second-phase viral decline larger than 1 log10 IU/mL/week.6-9

In order to gain insights into the faster second-phase decline observed with HCV protease inhibitors, we reanalyzed data from 44 patients treated with telaprevir,6 using a new viral kinetic model that accounts for the changes in drug pharmacokinetics/pharmacodynamics (PK/PD). Using the viral kinetic parameters found in this group of patients as a representative sample of naïve genotype 1 patients under telaprevir therapy, and assuming that drug resistance could be avoided, we estimated the treatment time needed to eliminate all virus and infected cells.

Results

Although both the CE and VE models provided good fits to the data at all drug doses used (Supporting Fig. S1), the VE model yielded significantly better fits when assessed by the Akaike information criterion, which allows one to compare the ability of models with different numbers of parameters to fit experimental data (Table 1). Because the VE model gave better fits, we only discuss results obtained with the VE model.

In principle, model parameters may vary according to treatment group. In particular, the parameters related to treatment effectiveness (e.g., k, ∈1, and ∈2) could be different in the telaprevir plus PEG-IFN, compared to the telaprevir monotherapy, group. However, no significant effect was found for any of the viral dynamic or drug effectiveness parameters (all P values >0.2).

We estimated that the initial treatment effectiveness, ∈1 = 0.974, increased and reached a significantly higher effectiveness, ∈2 = 0.999 (P < 0.0001), after approximately 1 day (Supporting Fig. S2). Furthermore, we estimated that there was a small delay, t0, before drug became effective (see Patients and Methods), which was estimated to have nearly the same value in all the patients: t0 = 0.10 days or 2.4 hours.

As reported previously,6 we found that the mean value of δ was high, compared to what has been reported with IFN-based treatments (Fig. 1). However, our estimate of δ is much lower than what was found using the CE model (mean: 0.58 versus 1.19 day-1 in the CE model). Moreover, our estimated value of δ is similar in monotherapy patients (0.58 day-1) and in patients receiving combination therapy (0.57 day-1), thus resolving the apparent paradox of a slower second-phase decline when PEG-IFN was added to telaprevir that was previously reported.6

Because only the first 3 days of treatment were analyzed, we checked whether our estimates would remain unchanged when including later time points (days 6, 10, and 13) in patients treated with telaprevir plus PEG-IFN and in whom no resistant virus was detected.16 Interestingly, we found no significant differences in this subset of patients in the loss rate of infected cells, δ, as compared to the original data set limited to 3 days of treatment (P = 0.49, t test), and the population parameters remained unchanged.

Because the rate of second-phase viral decline was larger in this study using telaprevir than in previous studies using IFN-based therapies, we asked whether the high effectiveness of telaprevir could play a role. We found that δ was significantly correlated with the final treatment effectiveness, ∈2 (r = 0.79, P < 0.001) (Fig. 2A). Thus, for patients in whom drug effectiveness was higher, not only did the first phase bring viral levels down lower, but also the second-phase slope was larger. Adiwijaya et al.,17 although they did not directly explore a correlation between ∈ and δ, found that allowing δ to increase with the telaprevir effectiveness, acccording to a relationship analogous to that shown in Fig. 2A, resulted in a better fit of their model to patient viral-load data. This finding not only supports the correlation we found, but shows its utility in data analysis.

Next, we asked whether this relationship between second-phase slope and treatment effectiveness was only true for telaprevir or whether it had wider applicability. To assess this, the relationship between drug effectiveness and δ was examined, both for the patients in this study and for patients from earlier studies involving treatment-naïve genotype 1 Caucasian patients receiving a high daily dose of IFN (>10 MIU).2, 3, 18 Recent analyses have demonstrated an association between interleukin (IL)-28B genotype and slopes of viral decline.19 Because the samples used here were not be tested for the IL-28B genotype, we restricted our analysis to Caucasians, for whom the chances to carry the favorable alleles are the highest.19 Combining the data from these studies with that from the telaprevir studies, we encompass a much larger range of drug-effectiveness values. We still find a significant positive correlation (r = 0.78, P < 0.001) between drug effectiveness and δ (Fig. 2B). However, further analyses will be necessary to identify precisely whether polymorphisms in the IL-28B gene may affect the relationship between the first and second phases of viral decay in patients treated with IFN.

Interestingly, the second-phase slope in patients treated with telaprevir is much less variable than what was seen with IFN-based treatment. Because δ almost entirely determines the second phase of viral decline (see Patients and Methods), this finding suggests that duration of therapy needed to eliminate all virus and infected cells might be considerably shortened, as compared to IFN-based therapies. We evaluated empirically the distribution function of the time needed to achieve less than one virion in the extracellular body water (see Patients and Methods). We predict that with full patient compliance, 95% of patients could achieve viral clearance within 7 weeks and 99% within 8 weeks (Fig. 3). This time could be significantly delayed, if all drug doses are not taken. For patients taking three doses a day, we estimated that if 16% of doses are randomly missed (i.e., one every 2 days, on average), the time needed to eradicate the virus in 95 and 99% of patients would increase to 9 and 11 weeks, respectively (Fig. 3). If more drug doses are missed or if the missed doses are clumped together, as in a weekend drug holiday, a longer time to eradication should be anticipated (not shown).

Under treatment, each cell, on average, may generate less than one HCV RNA per day. Furthermore, the clearance rate of virions is much faster than that of cells, and thus when all viruses have been cleared, some infected cells may still be present. If SVR is defined as the time to eliminate all infected cells, SVR could be delayed. Because only HCV RNA is observed, the estimated number of infected cells is based, in part, on the rate of viral production per infected cell under treatment, p(1 - ∈) in Equation 1. Because only the ratio (1 - ∈) of the viral production before and during treatment can be estimated, but not the viral production rate itself (p in Equation 1), we considered the values, p = 10 virions/day and p = 100 virions/day, that cover the range of p values found in a previous study in patients treated with telaprevir.20 With lower rates of viral production per infected cell, p, more infected cells are needed to explain the observed level of viremia in patients and hence the longer the time needed to eradicate the last infected cell. Based on these values of p, 2-3 additional weeks of treatments would be needed in order to eradicate all infected cells (Table 2).

 
Discussion
 
Using a new viral kinetic model that allowed for an improved description of the changes in antiviral treatment effectiveness, the second phase of viral decay was found to be very rapid, compared with second phases observed in patients treated with IFN alone, with no differences according to treatment regimen. More precisely, we estimated that telaprevir induced a four-fold more rapid second-phase viral decline than IFN-based therapy.2, 3 Because the current understanding of HCV RNA decay attributes the second phase of viral decline to the loss rate of infected cells, our result suggests that either cell death is enhanced or mechanisms of infected cell loss other than cell death may be operating. Yet, because no elevation in alanine aminotransferase, a surrogate marker of liver cell death, was reported during telaprevir-based therapy, the assumption that the enhanced loss rate of infected cells reflects an elevation in the cell death is unlikely.

The current explanation of HCV RNA decline under therapy comes from studies using moderately potent IFN treatment. In that context, assuming that, after a short delay, the viral production rate per infected cell is reduced under treatment by a constant factor, (1 - ∈), has provided excellent fits to viral kinetic data from a variety of studies. Nevertheless, as a result of their very high pressure on intracellular replication, the new direct antiviral agents might be able to continuously reduce levels of intracellular viral RNA and, consequently, the viral production per infected cell in a treatment-effectiveness-dependent manner. This may also be the case for IFN, if its effectiveness is high enough. Although this remains speculative, some experiments using the replicon system support the suggestion that intracellular viral RNA not only initially declines by the factor (1 - ∈), but then continues to decline under protease inhibitor21 or IFN22 treatment. If the rate of viral production per infected cell is constantly reduced during therapy, the second slope of viral decline may reflect not only the rate of loss of infected cells, but also the rate at which viral production declines in infected cells.23 Hence, the higher chance for attaining SVR observed in patients with an initial rapid viral response24 could not only be due to a better immune response, but also to the progressive elimination of intracellular replication complexes resulting from a more potent antiviral treatment.

No matter what the biological mechanism, the rapid second-phase decline observed with telaprevir suggests that the duration of therapy needed to clear the infection might be considerably shortened, as compared to IFN-based therapies. Based on the extrapolation of the kinetics of decline estimated in our population study, we estimated that eradication of all virus particles could be reached within 7-9 weeks in 95% of patients. If SVR is considered to be achieved when the last infected cell has been cleared, rather than when the last virus is eliminated, an additional 2-3 weeks of therapy may be needed. This estimate is based on the current modeling assumption that the level of viral production under treatment in infected cells is reduced by a constant factor. In the framework of a model considering intracellular viral RNA, the progressive vanishing of viral replicative intermediates could lead to the "curing" of infected cells before infected cells die, which would reduce the time to SVR closer to the estimate, based on the last remaining virus particle. Also, our model is deterministic and thus does not consider explicitly the random nature of each possible event (e.g., cell infection, cell death, and virus clearance). Although an approach that includes the randomness of these processes would more accurately capture the probability distribution function for the time to HCV eradication at the individual level, it would not change the distribution function at the population level, where the law of large numbers applies and which was our primary object of study.

Although Fig. 2 shows a positive correlation between treatment effectiveness and second-phase slope, δ, one should not assume that the second-phase slope would continue to increase as drug combinations become increasingly effective. In principle, at some point, the rate of loss of the infected state would be limited by host cell processes, such as the intrinsic rate at which replication complexes decay, and thus would no longer increase with therapy effectiveness. Also, other viral kinetics studies will be necessary to determine whether the relationship in Fig. 2 is true for other protease inhibitors. The second slope of viral decline has been reported for two other protease inhibitors-TMC-430 and danoprevir-and both studies reported a δ value roughly two times slower.8, 9

Another limitation of our calculation of treatment duration is that we assume no loss of drug effectiveness throughout the course of treatment. With this assumption, the rate of second-phase decline is predicted not to decrease during treatment. Is this assumption reasonable with current therapeutic strategies? Based on the high turnover rate of virus and the high error rate of the HCV RNA-dependent RNA polymerase, it has been predicted that all possible single- and double-virus mutants are present at treatment initiation.20 Thus, to avoid resistance emergence, combination therapy would be needed. Because a single-nucleotide substitution could be sufficient to confer resistance to protease inhibitors, the first treatment strategies that are expected to gain regulatory approval would be based on using a protease inhibitor (telaprevir or boceprevir) in combination with the standard of care (SOC). Because only approximately 50% of genotype 1 patients respond sufficiently strongly to the SOC to attain SVR, approximately 50% of genotype 1 patients treated with the current generation of protease inhibitors and SOC may not have a potent enough regimen to fully suppress the growth of protease-inhibitor resistance variants. This should also be the case in the majority of patients who already have failed prior regimens with SOC. Although resistant virus may not grow rapidly enough to cause viral breakthrough,23 they can slow the second-phase decline, as suggested by the relationship between ∈ and δ in Fig. 2, and hence lead to a need for a longer treatment duration. Consistent with this argument, posttreatment relapse with resistant virus has been seen in patients treated with telaprevir and SOC for 12 weeks.25, 26 Nucleoside polymerase inhibitors present a high genetic barrier to resistance,27 but their antiviral activity has tended, so far, to be much lower than protease inhibitors.27 Using a protease inhibitor and a second DAA constitute the natural next step of anti-HCV treatment strategies. Recent results showed high rates of rapid viral response, with no or low prevalence of resistance emergence for up to 4 weeks when the second DAA was a polymerase inhibitor and up to 12 weeks when the second DAA was an NS5A inhibitor.28-31 However, the fact that a resistance-related viral breakthrough occurred in some patients when SOC agents were not added to these cocktails hints that resistant virus may not be suppressed, but only reduced when two DAAs are used.28, 29, 32 Most likely, to attain SVR in 95% of treatment-compliant patients with a 10-week course of therapy would require treatments with three or more DAAs, including RBV. Clearly, at present, there are no approved regimens that meet our criteria of high potency and a high enough barrier to resistance.

Even if resistance was avoided by using an appropriate combination of DAAs, other factors might affect our prediction. First, the ability of IFN-sparing antiviral strategies to reach every viral population residing in the liver or in extrahepatic reservoirs is unknown. Second, the combination of several DAAs might increase toxicity and thus the adherence to treatment. How this may impact treatment duration has only been touched on in this study, and more data are needed to understand how the lack of adherence to treatment may favor the appearance and persistence of resistant virus.

Thus, attainment of SVR in less than 10 weeks in 95% of fully compliant patients would require combination drug regimens (1) that have a genetic barrier high enough so that resistance is avoided, (2) that have high drug penetration into all anatomical sites that contain infected cells, and (3) for which the pharmacokinetics of the drugs in the regimen allow the effectiveness of the regimen against viral production to be maintained at high levels throughout the course of treatment.

In summary, our finding that the second-phase slope increases with the effectiveness of therapy and our expectation that a combination of DAA agents will suppress the growth of drug-resistant variants holds open the promise that more effective therapies that use combinations of DAA agents may, one day, lead to SVR with treatment durations of 2-3 months.

Source