October 3, 2012

Next-Generation Protease Inhibitor Effective for HCV Infection

Patients who received vaniprevir achieved higher rapid virologic response rates than those who received placebo.

Adding telaprevir and boceprevir to standard peginterferon and ribavirin therapy has been shown to significantly improve virologic response rates for patients with genotype 1 hepatitis C virus (HCV) infection (JW Gastroenterol Jul 1 2011 and JW Gastroenterol Mar 30 2011). However, these first-generation HCV nonstructured protein (NS)3/4A protease inhibitors require a complex administration schedule and are associated with additional adverse effects.

To evaluate the efficacy and safety of vaniprevir (MK-7009) — a macrocyclic next-generation HCV NS3/4A protease inhibitor that is administered once or twice daily — investigators conducted an industry-funded, phase II, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study involving 94 treatment-naive adults with chronic HCV genotype 1 infection. Patients were assigned to vaniprevir (300 mg twice daily, 600 mg twice daily, 600 mg daily, or 800 mg daily) or matched placebo in combination with peginterferon (180 μg weekly) and ribavirin (1000–1200 mg daily) for 4 weeks. Thereafter, all patients continued peginterferon and ribavirin for 44 weeks. The primary endpoint was rapid virologic response (RVR); exploratory endpoints included sustained virologic response (SVR).

All 94 patients completed the 4-week triple-dosing regimen. Of these, 78 completed 48 weeks of peginterferon and ribavirin treatment, and 84 completed a 6-month post-therapy follow-up. The rate of viral decline by week 4 was at least 3log10 IU/mL greater in the vaniprevir groups versus the placebo group. Rates of RVR were significantly higher in all vaniprevir groups versus the placebo group (68.8%–83.3% vs. 5.6%; P<0.001). SVR rates were nonsignificantly higher in the vaniprevir groups than the placebo group (61.1%–84.2% and 63.2%, respectively), likely due to the small sample size. Safety profiles were similar between the vaniprevir and placebo groups, except vomiting occurred more often in the vaniprevir groups. HCV resistance variants were noted in three patients receiving vaniprevir.

Comment: This phase II study of vaniprevir shows early promise for a next-generation protease inhibitor–based triple therapy that is easy to administer in a daily or twice-daily dosing schedule. Subsequent vaniprevir studies are needed to identify the optimal dose and duration of therapy to maximize SVR and maintain an excellent safety profile.

Atif Zaman, MD, MPH

Published in Journal Watch Gastroenterology September 28, 2012

Citation(s):

Manns MP et al. Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: A randomized phase II study. Hepatology 2012 Sep; 56:884. (http://dx.doi.org/10.1002/hep.25743)

Medline abstract (Free)

Source

Philadelphia, PA, Monday, October 01, 2012: Hemispherx Biopharma, Inc. (NYSE MKT: HEB) (the “Company” or “Hemispherx”), announced that the Company has filed with ANMAT (Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica), the agency responsible for the national regulation of drugs, foods and medical technology in Argentina, an amended NDA for the use of its natural-source Alferon N Injection® (under the brand name “Naturaferon”) in patients with chronic hepatitis C who have become refractory to recombinant interferon as a result of the appearance of neutralizing antibodies (NABs) against recombinant interferon. As previously announced, ANMAT has already approved the sale of Naturaferon in Argentina for the treatment of refractory or recurring external condylomata acuminata (genital warts).

Thomas Equels, Vice Chairman of Hemispherx, stated, “Hepatitis C affects over 800,000 people in Argentina with a particularly high prevalence in rural communities. Worldwide it is a major health problem with more than 170 million people infected. In a very high percentage of cases chronic infection eventually leads to cirrhosis and hepatocellular carcinoma. Because patients with hepatitis C who become refractory to recombinant interferon have few alternatives, Hemispherx hopes ANMAT will approve the amended NDA. There is no assurance, however, that ANMAT will approve the amended NDA.”

Jorge Braver, President of GP Pharm, Hemispherx’s marketing partner in Argentina, said “We are very excited about this opportunity to seek ANMAT approval of this additional indication for Alferon N Injection® in Argentina.”

In a recent peer-reviewed article published in the Journal of Interferon and Cytokine Research (Volume 32, pages 95-102; http://online.liebertpub.com/doi/pdfplus/10.1089/jir.2011.0069), Hemispherx provided an analysis of the incidence and clinical impact of NABs formed during treatment with recombinant interferons compared to natural interferons, such as Alferon N Injection®, across a wide range of human diseases. The fraction of relapsed and refractory patients was reported as statistically greater in NAB positive patients compared to NAB negative patients (p < 0.0001), whereas the percentage of responding patients was reported as higher in NAB negative patients (p < 0.001). Another analysis looked at relapsed and refractory NAB positive patients who were then switched to natural interferon. Across all the different diseases the authors reviewed, 33 out of 40 or 82% of these patients had their clinical response restored after switching to natural interferon.

The Company also reported that it renewed its agreement in the U.S. with Armada Health Care, LLC (“Armada”) (www.armadahealthcare.com) for the sales/marketing of Alferon N Injection®. Under this Agreement, once manufacturing of Alferon N Injection® recommences, the Company will manufacture and supply Alferon N Injection® to physicians and patients through Armada’s national network of specialty pharmacies.

DISCLOSURE NOTICE: The information in this press release includes certain “forward-looking” statements (explained below), including statements about the steps to potentially gain ANMAT approval of Alferon N Injection® for the treatment of hepatitis C. The final results of these and other ongoing activities could vary materially from Hemispherx’s expectations and could adversely affect the chances for ANMAT approval of Alferon N Injection® for this indication. These activities and the ultimate outcomes are subject to a variety of risks and uncertainties, including but not limited to risks that (i) that the application may not be accepted by ANMAT or such acceptance may be delayed and (ii) ANMAT may ask for additional data, information or studies to be completed or provided prior to approval. Any failure to satisfy ANMAT’s requirements could significantly delay, or preclude outright, approval of Alferon N Injection® for hepatitis C in Argentina.

About Hemispherx Biopharma

Hemispherx Biopharma, Inc. is an advanced specialty pharmaceutical company engaged in the manufacture and clinical development of new drug entities for treatment of seriously debilitating disorders. Hemispherx’s flagship products include Alferon N Injection® and the experimental therapeutics Ampligen® and Alferon® LDO. Ampligen is an experimental RNA nucleic acid being developed for globally important debilitating diseases and disorders of the immune system, including Chronic Fatigue Syndrome. Hemispherx’s platform technology includes components for potential treatment of various severely debilitating and life threatening diseases. Hemispherx has patents comprising its core intellectual property estate and a fully commercialized product (Alferon N Injection®), approved for sale in the U.S. for refractory or recurring external genital warts in patients 18 years of age or older. The Company wholly owns and exclusively operates a GMP certified manufacturing facility in the United States for commercial products. For more information please visit www.hemispherx.net.

About GP Pharm

GP Pharm SA headquarters are located in Barcelona, Spain with operations in each major country in Latin America either directly or through local partners. Its activities are focused on research, development and marketing of injectable products made by others and by GP Pharm SA based on its proprietary drug delivery systems including microspheres and liposomes. GP Pharm’s new production plant recently achieved EU GMP approval and started manufacturing operations, producing the first batches of own products and also for some contract manufacturing partners. Its facilities are also designed to be FDA GMP compliant. GP Pharm has a centralized free-zone distribution facility in Uruguay for its own products as well as its partners’ products.

Contact:
Hemispherx Biopharma, Inc.,
Dianne Will, Investor Relations
(518) 398-6222,
ir@hemispherx.net
HEB's Web Site: www.hemispherx.net

Forward-Looking Statements

To the extent that statements in this press release are not strictly historical, all such statements are forward-looking, and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Words such as “hopes,” “believes,” “plans,” “anticipates,” and similar expressions are intended to identify forward-looking statements. These statements are based on the Company’s current beliefs and expectations and represent the Company’s judgment as of the date of this release. The inclusion of forward-looking statements should not be regarded as a representation by Hemispherx that any of its plans will be achieved. These forward-looking statements are neither promises nor guarantees of future performance, and are subject to a variety of risks and uncertainties, many of which are beyond Hemispherx’s control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. Examples of such risks and uncertainties include those set forth in the Disclosure Notice, above, as well as the risks described in Hemispherx’s filings with the Securities and Exchange Commission, including the most recent reports on Forms 10-K, 10-Q and 8-K. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Hemispherx undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise revise or update this release to reflect events or circumstances after the date hereof.

Source

Coffee and Liver – Long Way To Go

Journal of Clinical & Experimental Hepatology
Volume 2, Issue 3 , Pages 291-294, September 2012

Ajay K. Duseja (Section Editor)

Chandigarh, India

Received 12 July 2012; accepted 12 July 2012. published online 26 July 2012.

Abbreviations: HCC, Hepatocellular carcinoma, IQR, interquartile range, CC, Caffeine consumption, NAFLD, Nonalcoholic fatty liver disease, NHANES, National Health and Nutrition Examination Surveys, CHC, Chronic hepatitis C, LDL, Low-density lipoprotein

Abstract 1

Johnson S, Koh WP, Wang R, Govindarajan S, Yu MC, Yuan JM. Coffee consumption and reduced risk of hepatocellular carcinoma: Findings from the Singapore Chinese Health Study. Cancer Causes Control. 2011; 22:503–510.

The Masonic Cancer Center, MMC 806, University of Minnesota, 425 East River Road, Minneapolis, MN 55455, USA.

Background: Coffee consumption has been associated with reduced markers of hepatic cell damage, reduced risk of chronic liver disease, and cirrhosis across a variety of populations. Data on the association between coffee consumption and risk of hepatocellular carcinoma (HCC), especially in high-risk populations, are sparse. Methods: This study examines the relationship between coffee and caffeine consumption, and the risk of developing HCC within the Singapore Chinese Health Study, a prospective cohort of 63,257 middle-aged and older Chinese men and women, a relatively high-risk population for HCC. Baseline data on coffee consumption and other dietary and lifestyle factors were collected through in-person interviews at enrollment between 1993 and 1998. Results: As of 31 December 2006, 362 cohort participants had developed HCC. High-levels of coffee or caffeine consumption were associated with reduced risk of HCC (P for trend <0.05). Compared with nondrinkers of coffee, individuals who consumed three or more cups of coffee per day experienced a statistically significant 44% reduction in risk of HCC (hazard ratio 0.56, 95% confidence interval, 0.31–1.00, P = 0.049) after adjustment for potential confounders and tea consumption. Conclusion: These data suggest that coffee consumption may reduce the risk of developing HCC in Chinese in Singapore.

Abstract 2

Freedman ND, Curto TM, Lindsay KL, Wright EC, Sinha R, Everhart JE; HALT-C TRIAL GROUP. Coffee consumption is associated with response to peginterferon and ribavirin therapy in patients with chronic hepatitis C. Gastroenterology. 2011;140:1961–1969.

Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD 20852, USA.

Background & aims: High-level coffee consumption has been associated with reduced progression of pre-existing liver diseases and lower risk of hepatocellular carcinoma. However, its relationship with therapy for hepatitis C virus infection has not been evaluated. Methods: Patients (n = 885) from the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial recorded coffee intake before retreatment with peginterferon α-2a (180 μg/wk) and ribavirin (1000–1200 mg/day). We assessed patients for early virologic response (2 log10 reduction in level of hepatitis C virus RNA at week 12; n = 466), and undetectable hepatitis C virus RNA at weeks 20 (n = 320), 48 (end of treatment, n = 284), and 72 (sustained virologic response; n = 157). Results: Median log10 drop from baseline to week 20 was 2.0 (interquartile range [IQR], 0.6–3.9) among nondrinkers and 4.0 (IQR, 2.1–4.7) among patients that drank 3 or more cups/day of coffee (P trend <0.0001). After adjustment for age, race/ethnicity, sex, alcohol, cirrhosis, ratio of aspartate aminotransferase to alanine aminotransferase, the IL28B polymorphism rs12979860, dose reduction of peginterferon, and other covariates, odds ratios for drinking 3 or more cups/day vs nondrinking were 2.0 (95% confidence interval [CI]: 1.1–3.6; P trend = 0.004) for early virologic response, 2.1 (95% CI: 1.1–3.9; P trend = 0.005) for week 20 virologic response, 2.4 (95% CI: 1.3–4.6; P trend = 0.001) for end of treatment, and 1.8 (95% CI: 0.8–3.9; P trend = 0.034) for sustained virologic response. Conclusions: High-level consumption of coffee (more than 3 cups per day) is an independent predictor of improved virologic response to peginterferon plus ribavirin in patients with hepatitis C.

Abstract 3

Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DM, Harrison SA. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology. 2012;55:429–436.

Division of Gastroenterology and Hepatology, Wilford Hall Medical Center, Lackland Air Force Base, TX, USA.

Coffee caffeine consumption (CC) is associated with reduced hepatic fibrosis in patients with chronic liver diseases, such as hepatitis C. The association of CC with nonalcoholic fatty liver disease (NAFLD) has not been established. The aim of this study was to correlate CC with the prevalence and severity of NAFLD. Patients involved in a previously published NAFLD prevalence study, as well as additional NASH patients identified in the Brooke Army Medical Center Hepatology clinic, were queried about their caffeine intake. A validated questionnaire for CC was utilized to assess for a relationship between caffeine and four groups: ultrasound negative (controls), bland steatosis/not-NASH, NASH stage 0–1, and NASH stage 2–4. A total of 306 patients responded to the CC questionnaire. Average milligrams of total caffeine/coffee CC per day in controls, bland steatosis/not-NASH, NASH stage 0–1, and NASH stage 2–4 were 307/228, 229/160, 351/255, and 252/152, respectively. When comparing patients with bland steatosis/not-NASH to those with NASH stage 0–1, there was a significant difference in CC between the two groups (P = 0.005). Additionally, when comparing patients with NASH stage 0–1 to those with NASH stage 2–4, there was a significant difference in coffee CC (P = 0.016). Spearman's rank correlation analysis further supported a negative relationship between coffee CC and hepatic fibrosis (r = −0.215; P = 0.035). Conclusion: Coffee CC is associated with a significant reduction in risk of fibrosis among NASH patients.

Abstract 4

Birerdinc A, Stepanova M, Pawloski L, Younossi ZM. Caffeine is protective in patients with nonalcoholic fatty liver disease. Aliment. Pharmacol Ther. 2012;35:76–82.

Center for Liver Disease and Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA; School of Systems Biology, College of Science, George Mason University, Fairfax, VA, USA; and Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA.

Background: Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, is the most common cause of primary liver disease. Although recent studies have found that coffee drinking is protective against end stage chronic liver disease, there are scarce caffeine intake data in NAFLD specifically. Aim: To investigate the effects of dietary behavior in NAFLD patients, using four continuous cycles of the National Health and Nutrition Examination Surveys (NHANES 2001–2008). Methods: Using data from four continuous cycles of NHANES, dietary intake questionnaires that list 62 nutrition components. Logistic regression was used to identify independent predictors of NAFLD among nutrition components after adjustment for potential clinical confounders. All analyses were run using SAS 9.1 and SUDAAN 10.0 (SAS Institute Inc., Cary, NC, USA). Results: Of the 62 nutrient components used for the univariate analysis, 38% were significant (P-value <0.05) in NAFLD with caffeine consumption being higher in the control group (P-value <0.001). The multivariate analysis using demographics, clinical parameters and nutritional components found five factors independently associated with NAFLD [African American Race (P-value <0.001); Male gender (P-value <0.001); Obesity (BMI ≥ 30) (P-value <0.001); Caffeine intake (mg) (P-value <0.001) and total plain water consumption (g) (P-value ≤0.02)]. Conclusions: Our analysis shows that caffeine intake is independently associated with a lower risk for NAFLD suggesting a potential protective effect. These data necessitate further research to elucidate the mechanism by which caffeine can protect against NAFLD.

Comments

Although, beneficial health effects of coffee are controversial, a large population-based study found that increased coffee intake decreased all-cause mortality, largely due to a reduced rate of cardiovascular death.1 As far as the liver disease is concerned, population-based studies have shown lower risk of raised transaminases and chronic liver disease with higher caffeine consumption (>2 cups per day).2, 3 In addition, coffee has been reported to reduce the risk of advanced liver disease and its complications including hepatocellular carcinoma (HCC).4 Recent data has suggested that the higher caffeine consumption is associated with lower rates of progression of fibrosis in patients with chronic liver disease, particularly those related to alcohol and chronic hepatitis C (CHC).5 Relationship of hepatic fibrosis with coffee consumption is significant in view of the fact that the reduction of fibrosis progression in chronic liver disease would potentially help prevent the associated complications of cirrhosis and HCC.

The Singapore Chinese Health Study6 (Abstract 1) evaluated the relationship between coffee and caffeine consumption, and the risk of developing HCC in a prospective cohort of 63,257 middle-aged and older Chinese men and women, a relatively high-risk population for HCC. Baseline data on coffee consumption and other dietary and lifestyle factors were collected through in-person interviews at enrollment. Out of 63,257 subjects enrolled in five years, 362 participants had developed HCC. High-levels of coffee or caffeine consumption were associated with reduced risk of HCC (P for trend <0.05). Compared with nondrinkers of coffee, individuals who consumed three or more cups of coffee per day experienced a statistically significant 44% reduction in risk of HCC (hazard ratio 0.56, 95% confidence interval, 0.31–1.00, P = .049) after adjustment for potential confounders and tea consumption.

Most of the earlier data on the association of coffee and HCC are available from low prevalence areas. The results from the present study are significant to confirm that coffee consumption may reduce the risk of developing HCC even in population with higher risk of developing HCC. 6 Coffee has more than a 1,000 compounds, with caffeine being the major constituent. It is postulated that the liver-protecting properties of coffee come from two of the coffee oils (called dipterenes): cafestol and kahweol. Even though the exact mechanism is unknown, animal studies suggest that some of the coffee compounds including cafestol, and kahweol, may act as blocking agents via modulation of multiple enzymes involved in carcinogenic detoxification.7, 8 They also modify the xenotoxic metabolism via induction of glutathione-S-transferase and inhibition of N-acetyltransferase.9 Coffee has also been found to reduce the risk of hepatic fibrosis and cirrhosis, a major risk in the process of liver carcinogenesis.4 Thus, the beneficial effect of coffee consumption on HCC may also be due to its inverse relation with hepatic fibrosis and cirrhosis.

Freedman et al10 looked at an entirely new concept i.e. the effect of coffee on the response to HCV therapy in patients with CHC (Abstract 2). Interestingly they found that high-level consumption of coffee (more than 3 cups per day) was an independent predictor of improved virologic response to peginterferon plus ribavirin in patients with CHC.10 Patients (n = 885) from the lead-in phase of the HALT-C Trial recorded coffee intake before retreatment with peginterferon α-2a and ribavirin. The higher virological response in coffee drinkers is unlikely to be a direct antiviral effect and is more likely a facilitating effect on response to peginterferon and ribavirin treatment by a mechanism yet to be understood. The antiviral affect may be related to the link between kahweol in coffee to JAK-STAT signaling which is associated with the IL28B genotype effect on virological response.11 Coffee intake may also cause increased virological response to therapy by increasing the serum total cholesterol and low-density lipoprotein (LDL) which has been linked with higher virological response.12 Further, coffee intake may improve insulin resistance and thus affect the virological response.13

Even though coffee consumption was shown to be associated with reduced hepatic fibrosis in patients with CHC, the association with nonalcoholic fatty liver disease (NAFLD) was not well established. Molloy et al14 in a recent issue of Hepatology (Abstract 3) showed an inverse relationship between regular coffee consumption and hepatic fibrosis in patients with NAFLD with a statistically significant difference in caffeine coffee intake observed between ultrasound negative controls, bland steatosis/not-NASH patients, NASH stage 0–1 fibrosis patients, and NASH stage 2–4 fibrosis patients. Importantly, on multiple statistical analyses, the trend of increased coffee caffeine intake and decreased fibrosis remained statistically significant.14 Though patients with bland steatosis/not-NASH, as well as the control group, drank less coffee than those patients with NASH stage 0–1 fibrosis, it was not clear what amount of coffee confers the greatest decreased risk of fibrosis. The beneficial effects of caffeine intake and association with lower risk for NAFLD suggesting a potential protective effect are reinforced in the study by Birerdinc et al15 (Abstract 4) who on evaluating dietary behavior in NAFLD patients found significantly higher caffeine consumption in the control group as compared to patients with NAFLD.

The beneficial effect of caffeine/coffee in patients with NAFLD may be related to its antioxidant activity.16 The dipterenes, kahweol and cafestol, the constituents of coffee though have been shown to have beneficial effects on glutathione metabolism; these oils have also been shown to increase cholesterol levels, a finding that may not be beneficial to patients with NAFLD.12, 17 Caffeine also inhibits expression of connective tissue growth factor by interfering with transforming growth factor beta signaling and by up-regulating peroxisome proliferator-activated receptor gamma levels, which could explain the antifibrogenic effects of caffeine.18

While we can go on discussing as to the number of cups of coffee which are likely to provide benefit, we need to know what our cup of coffee really contains. There are various types of coffee and most commercially available coffee beverages consumed around the world are produced by the species Coffea arabica (Arabica) and Coffea canephora (Robusta) each of which has various varieties. The composition of coffee varies with the species and with the process of maturation. The caffeine content of the coffee beans depends on species and variety, from 0.6% in Laurina of Coffea arabica up to >4% in Robusta variety of Coffea canephora. The caffeine content of coffee can be reduced by decaffeination, a process which involves steam treatment of the green coffee to soften the tissues, followed by solvent extraction. The type of preparation of the cup of coffee also matters. In an expresso-type percolation, the very short time available to extract caffeine from the cellular structure leads to 75–85% extraction yield only.19

Many questions however remain unanswered before we conclude that coffee can take care of our livers. Amount of coffee, and type of coffee no doubt would be important but equally important might be the race of the population being studied for the beneficial effects of coffee. Although more than 3 cups of coffee look protective, more data on this issue are required before the protective amount of coffee is decided. Is it all caffeine or other constituents of coffee doing the job? Is it the antioxidant effect of coffee and its constituents or something else? And finally there has been lot of focus on the protective effects of coffee oils i.e. cafestol, and kahweo, most of which are filtered out in traditional American coffee, and, therefore the population may not really be exposed to them. So while we can look at our cup of coffee with exhilaration, is it the right one for our liver?

A number of studies have reported the beneficial effects of coffee on abnormal liver biochemistry, cirrhosis, hepatocellular carcinoma and NAFLD. However, the exact mechanism of these effects remains unclear as does the ‘‘dose’’ required to achieve these benefits.20 It seems a long way to go till we get all the answers.

References

Source

Medications and the Liver

Overview

Introduction

One of the main functions of the liver is to break down substances that we take by mouth, including medications, herbs and supplements. This process usually takes place efficiently and without causing any harm. When new medications are developed, they are extensively tested in many people prior to being approved for general use. During this period careful tests are done to ensure that the liver is not damaged. For this reason, the vast majority of the medications currently available are safe even for people with known liver disease.

Despite these safeguards sometimes medications can harm the liver. In some instances, a person can have a rare tendency that makes their liver susceptible to injury after taking a certain medication – we call this an idiosyncratic reaction. It happens in very rare instances and often cannot be predicted. Occasionally, medications that proved safe during testing are found to be potentially harmful when they are released for general use and millions of people take it. In other instances, people with liver disease may be at increased risk of developing liver damage when certain medications are used. Medications that are known to be toxic to people with liver disease usually carry a warning regarding its use in people with liver problems.

What are the symptoms of medication-related liver injury?

In most cases substantial liver damage can occur before symptoms appear. Typical symptoms of liver disease may include malaise, nausea, lack of appetite, discomfort on the right upper corner of the abdomen, generalized itching, dark urine and jaundice (yellow discoloration of the eyes and skin), but many people have no symptoms at all. Blood tests can usually detect evidence of liver damage before symptoms develop. When a medication known to possibly cause liver damage is used, your physician may recommend that blood tests be checked periodically after starting the medication so that any evidence of liver damage can be detected before symptoms appear.

What blood tests are used to detect liver damage from medications?

Usually there is no need to monitor the liver tests when a medication is started. If your physician is planning on using a medication that in the past has been shown to rarely cause liver damage, the most common test used to monitor the liver is a liver panel, which consists of several blood tests that detect liver damage. These tests are: AST (aspartate aminotransferase), ALT (alanine aminotransferase), AP (alkaline phosphatase) and bilirubin. There are many other causes for elevated liver tests. For that reason your physician may obtain a baseline liver panel prior to starting a medication to be sure that it is normal.

Minor elevations of these tests may occur after starting a medication and do not indicate significant liver damage. Generally speaking physicians are most concerned about medication-induced liver damage when the levels of AST and ALT rise 3 to 5 times or more over baseline or if there is an increase in bilirubin. If the elevations are minor, the medication is continued and the liver tests monitored. In most cases, the liver tests will return to normal despite continuing the medication.

What are some of the common medications that can cause liver damage?

Probably the best known medication that can damage the liver is acetaminophen, also known as Tylenol®. This medication is widely available without prescription and is present in many of the cold and flu remedies sold in drugstores as well as in prescription pain medications. Most pain medications that are labeled as “non-aspirin” have acetaminophen as its main ingredient.

Acetaminophen, when used as directed, is extremely safe even for people with liver disease. However, taking too much acetaminophen at once, or taking a high dose of acetaminophen continuously over several days can cause damage to the liver. Healthy individuals should not take more than 1,000 mg of acetaminophen per dose, and should not take more than 4,000mg in one day (i.e. maximum of 1,000 mg every 6 hours). In addition, even healthy persons should avoid taking 4,000mg of acetaminophen daily for more than 3 to 5 days. Patients with liver disease should restrict the daily amount of acetaminophen to 2,000mg per day, or even less if severe liver disease is present. Even if you have no liver disease, always use the smallest amount of acetaminophen needed to obtain relief.

People who drink alcoholic beverages regularly are at higher risk of developing severe liver damage from acetaminophen. Drinking alcohol regularly changes the way the liver breaks down certain medications. In the case of acetaminophen, alcohol use leads to accumulation in the liver of a toxic byproduct of acetaminophen that can kill the liver cells. People who drink alcohol regularly should not take acetaminophen or take it rarely if at all.

Do cholesterol lowering medications cause liver damage?

Another common group of medications that can affect the liver are the cholesterol lowering medications commonly known as “statins”; a group that includes many of the currently prescribed medications to lower cholesterol. These medications have been used in millions of people with an excellent safety record and very little evidence of liver damage, even when used in people with mild liver disease. It is not rare, however, for people to develop minor elevations of the liver tests soon after they start taking these medications. In the vast majority of cases, these elevations are less than 3 times the baseline level and the levels return to normal despite continued use of the medication. While it is a good idea to monitor the liver tests when these medications are started, the medication should not be stopped if only a minor elevation of liver tests is noted.

Can supplements and herbs cause liver damage?

Definitely! Supplements and herbs, despite being “natural” can be toxic to the liver. The production and distribution of these supplements is not regulated as carefully as the production of prescription medications. “Natural” products can be sold with little testing and with no proof of efficacy. Sometimes the herb or supplement itself can cause liver damage. In other cases, impurities or toxins introduced during the preparation of the product may be toxic to the liver. Some of the natural products known to be toxic to the liver include chaparral, comfrey tea, kava, skullcap, and yohimbe, but there are many others. Even vitamin supplements can be harmful if taken in excess. Too much iron or vitamin A can result is significant liver damage.

Are people with liver disease at increased risk of liver damage from medications?

With very rare exceptions, people that have mild liver disease can safely take most common prescription and non-prescription medications at the recommended dose. Having mild liver disease such as hepatitis C or fatty liver does not increase the risk that a given medication will be toxic to the liver, however, if a person with pre-existing liver disease happens to develop liver injury from a medication, the resulting liver damage may be more severe than would occur in an otherwise healthy person with the same reaction. For that reason, whenever possible, physicians prefer to use “liver-safe” medications when we know a person has liver disease.

People with more severe types of liver disease such as cirrhosis have to be more careful regarding the types and dose of medications they take. While the ability of the liver to properly break down and utilize medications is preserved even when severe liver disease is present, there are some medications that should not be used or should be used at reduced dose when given to patients with advanced cirrhosis.

What can I do to decrease the risk of liver damage from medications?

There are several things you can do:

  1. Always keep a list of all the prescription and non-prescription medications that you take, including herbs, vitamins and supplements. Bring this list with you to every physician’s appointment.
  2. The fewer medications you take the better. This includes herbs, supplements, prescription and non-prescription medications. If you have several physicians prescribing medications for you, be sure all of them are updated on your current list of medications.
  3. When using non-prescription medications, be sure to read the label carefully and never exceed the recommended amount. Avoid taking the maximum recommended dose for a prolonged period without consulting a physician.
  4. If you are taking several medications, be sure the ingredients are not the same; otherwise you may risk taking an accidental overdose.
  5. If you drink a significant amount of alcohol daily, avoid or restrict the use of acetaminophen; never take the maximum recommended dose.
  6. If you have liver disease, make sure that your physician is aware of your diagnosis and the severity of your liver disease.
  7. If you have advanced liver disease such as severe cirrhosis, it is a good idea to consult with the liver specialist before starting new medications.

Author

Jorge L. Herrera, MD, FACG, University of South Alabama College of Medicine, Mobile, AL

Source

Improving targeted screening for hepatitis C in the UK

BMJ2012;345doi: 10.1136/bmj.e6525 (Published 3 October 2012)

Cite this as: BMJ2012;345:e6525

  1. Christopher J A Duncan, research fellow1,
  2. Ewen Stewart, general practitioner2,
  3. Ray Fox, consultant in infectious diseases3

Author Affiliations

  1. 1Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
  2. 2Rose Garden Medical Centre, Edinburgh, UK
  3. 3Brownlee Centre for Infection, Tropical Medicine, and Counselling, Gartnavel Hospital, Glasgow, UK

chrisduncan@doctors.net.uk

Primary care practitioners can play an important role

A recent report from the Health Protection Agency in the United Kingdom estimates that 216 000 people, 90% of whom have injected drugs, are infected with the hepatitis C virus.1 Also at higher risk of infection are migrants from South Asia and eastern Europe and men who have sex with men.1 Of major concern is that half of the infected people who inject drugs who were surveyed (equivalent to nearly 100 000 people) were unaware of their diagnosis.1 This represents a huge burden of undiagnosed chronic hepatitis C in the UK and means that we should seriously consider targeted screening for hepatitis C. Such a shift in policy would have implications for primary care.

Targeted screening for hepatitis C fulfils World Health Organization criteria for screening.2 Because chronic infection has no specific symptoms, screening is the only way to identify people with hepatitis C before the onset of symptomatic liver disease. Serious complications such as cirrhosis develop in about 30% of chronically infected people after 20 years, and people who are infected with hepatitis who also have cirrhosis have a 5% annual risk of decompensated liver disease or hepatocellular carcinoma.3 Disease associated with hepatitis C infection is now a leading indication for liver transplantation.3 Hepatitis C related hospital admissions, deaths, and liver transplants have been rising steadily in the UK since 1996,1 and further substantial increases are projected. Treatment of chronically infected patients with pegylated interferon and ribavirin is a cost effective way to prevent these complications. Cure rates in clinical practice (40% for genotype 1, 70% for genotype 3) are comparable to rates seen in randomised trials,4 but treatment is associated with frequent and unpleasant side effects.

However, treatment is improving rapidly. Several new directly acting antivirals are available or are in advanced stages of development.5 The hepatitis C virus NS3/4A protease inhibitors boceprevir and telaprevir (recently approved by the National Institute for Health and Clinical Excellence; NICE) improve cure rates in patients with the more difficult to treat genotype 1 to 70% when given with standard treatment.3 In addition, interferon sparing regimens considerably improve tolerability of treatment, and clinical trials of combinations of directly acting antivirals without pegylated interferon show efficacy rates that are encouraging.5 Tolerable and effective treatments of short duration are likely to become available in the next few years, and treatment services will probably need to be expanded beyond what has already been achieved through the national hepatitis C action plans.

Undiagnosed infection remains an important barrier to treatment.1 Draft NICE guidelines currently under consultation recommend strategies to improve testing of people in high risk groups in various settings.6 Screening of people who currently inject drugs should take place in any setting, particularly drug services, whereas primary care is more appropriate for identifying and screening people who previously injected drugs.7 Testing has increased considerably in primary care in recent years.1 However, the proportion of positive tests is falling,1 which suggests that testing might be more efficiently targeted.

In clinical trials, primary care interventions to encourage case finding have increased uptake of testing and diagnosis.7 8 In the UK, the yield is greater when screening is targeted at high risk groups because the prevalence of hepatitis C in the general population (such as first time blood donors) is very low.1 A systematic review of economic evaluations provides evidence that screening in primary care is cost effective if targeted at high risk groups.9 Population age based screening, as advocated in the United States, is unlikely to be cost effective in regions like the UK, where population prevalence is lower.9 However, this does not mean that people who lack traditional risk factors should not be tested if there is clinical suspicion.

Successful interventions are not limited to people who inject drugs; community interventions to increase testing in South Asians in the UK have also shown acceptability and efficacy.10 Public education campaigns to raise awareness of hepatitis C have been instituted in recent years, and studies suggest that these campaigns are more effective when complemented by education and support in primary care.11 New technology, such as testing dry blood spots, improves uptake in people in whom venous access is difficult.1

However, case finding is unlikely to be beneficial unless sufficient numbers of infected people ultimately undergo successful treatment. Attendance at specialist clinics in the UK remains suboptimal. If screening in primary care is to translate into more patients being treated, it is crucial to increase attendance rates by strengthening treatment outreach programmes from secondary care and improving communication about the benefits of treatment.

Intervention studies support the acceptability of targeted screening, but previous qualitative studies have highlighted the need for sensible and appropriate pre-test and post-test counselling in vulnerable groups.12 Concerns about counselling should not become a barrier to testing, particularly given the clear benefit of curative treatment. Specific training in detecting and testing for viral hepatitis in primary care is offered through the Royal College of General Practitioners (www.elearning.rcgp.org.uk).

Much still needs to be done to improve care for people with hepatitis C in all healthcare settings by simultaneously expanding testing and increasing access to treatment. Targeted screening in primary care can form a major part of this effort.

Notes

Cite this as: BMJ 2012;345:e6525

Footnotes

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: CJAD is supported by a Wellcome Trust Research Training Fellowship (094449/Z/10/Z); RF and ES are clinical leads for the NHS Greater Glasgow and Clyde and NHS Lothian hepatitis C managed care networks, respectively; RF is a member of advisory boards for both Merck (boceprevir) and Janssen (telaprevir); ES is a member of the advisory board for Janssen (telaprevir); no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

References

  1. Health Protection Agency. Hepatitis C in the UK. 2012. www.hpa.org.uk/Publications/InfectiousDiseases/BloodBorneInfections/HepatitisCInTheUK/.

  2. Wilson JM, Jungner G. Principles and practice of screening for disease. WHO, 1968. http://whqlibdoc.who.int/php/WHO_PHP_34.pdf.

  3. Ramachandran P, Fraser A, Agarwal K, Austin A, Brown A, Foster GR, et al. UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients. Aliment Pharmacol Ther2012;35:647-62.

  4. Innes HA, Hutchinson SJ, Allen S, Bhattacharyya D, Bramley P, Carman B, et al. Ranking predictors of a sustained viral response for patients with chronic hepatitis C treated with pegylated interferon and ribavirin in Scotland. Eur J Gastroenterol Hepatol2012;24:646-55.

  5. Chung RT. A watershed moment in the treatment of hepatitis C. N Engl J Med2012;366:273-5.

  6. National Institute for Health and Clinical Excellence. Hepatitis B and C—ways to promote and offer testing. Draft guidance. 2012. http://guidance.nice.org.uk/PHG/29.

  7. Cullen BL, Hutchinson SJ, Cameron SO, Anderson E, Ahmed S, Spence E, et al. Identifying former injecting drug users infected with hepatitis C: an evaluation of a general practice-based case-finding intervention. J Public Health (Oxf)2012;34:14-23.

  8. Litwin AH, Smith BD, Drainoni ML, McKee D, Gifford AL, Koppelman E, et al. Primary care-based interventions are associated with increases in hepatitis C virus testing for patients at risk. Dig Liver Dis2012;44:497-503.

  9. Sroczynski G, Esteban E, Conrads-Frank A, Schwarzer R, Muhlberger N, Wrigt D, et al. Long-term effectiveness and cost-effectiveness of screening for hepatitis C virus infection. Eur J Public Health2009;19:245-53.

  10. Jafferbhoy H, Miller MH, McIntyre P, Dillon JF. The effectiveness of outreach testing for hepatitis C in an immigrant Pakistani population. Epidemiol Infect2012;140:1048-53.

  11. Helsper CW, van Essen GA, Bonten MJ, de Wit NJ. A support programme for primary care leads to substantial improvements in the effectiveness of a public hepatitis C campaign. Fam Pract2010;27:328-32.

  12. Tompkins CN, Wright NM, Jones L. Impact of a positive hepatitis C diagnosis on homeless injecting drug users: a qualitative study. Br J Gen Pract2005;55:263-8.

Source

Provided by NATAP

Download the PDF here

this study reports new HCV therapy can in the near future reduce cirrhosis & death by 50-280% in Western Europe (see graphs)....."this study also underlines the urgent need for reinforcement of HCV screening and access to therapy."

Gastroenterology October 2012

SYLVIE DEUFFIC-BURBAN,*, PIERRE DELTENRE,, MARIA BUTI, TOMMASO STROFFOLINI,# JULIE PARKES,** NIKOLAI MUHLBERGER, UWE SIEBERT,,, CHRISTOPHE MORENO, ANGELOS HATZAKIS,## WILLIAM ROSENBERG,*** STEFAN ZEUZEM, and PHILIPPE MATHURIN,

"In conclusion, the present study clearly shows the benefit of antiviral therapy in European countries, amplified by the use of PIs. The present data should help public health authorities to optimize the impact of such therapy on morbidity and mortality."

"the total number of patients with cirrhosis (including complications) is expected to peak in 2020 for Belgium, 2021 for France, 2023 for Germany, 2030 for Spain, and 2033 for the United Kingdom in the absence of treatment; for Italy, the peak was reached in 2008. These differences in fibrosis stage distribution over time are related to patterns of HCV infection. Belgium, France, and Germany present patterns similar to that predicted by Davis et al in the United States."

"The future expected regimen (assumed to be available in 2017) would considerably impact the overall HCV-related incidence of cirrhosis and death from 2017 to 2026, with an even greater effect with reinforcement of HCV screening and treatment access (Figure 4A and B). Detailed results are shown in Supplementary Table 7."

"From 2002 to 2011, antiviral therapy reduced the cumulative incidence of cirrhosis by 7.1% and deaths by 3.4% overall. Reductions in incidence and mortality values ranged from 4.0% and 1.9%, respectively, in Italy to 16.3% and 9.0%, respectively, in France. From 2012 to 2021, antiviral treatment of patients with HCV genotype 1 infection that includes protease inhibitor-based triple therapy will reduce the cumulative incidence of cirrhosis by 17.7% and mortality by 9.7% overall. The smallest reduction is predicted for Italy (incidence reduced by 10.1% and mortality by 5.4%) and the highest is for France (reductions of 34.3% and 20.7%, respectively)."

Figure 3 from Jules of NATAP: as you can see in Figure 3 improved access to treatment reduces cirrhosis & death 50-280%, and this analyses appear to only consider triple therapy with a PI+ Peg/Rbv, not even all oral 100% cure rates with 3-4 orals IFN-free therapy.

Treatment impact from 2012 to 2021 for G1: reduction in cumulative incidence of HCV-related (A) cirrhosis and (B) death for each country, considering pegylated bitherapy, PI-based triple therapy alone, or PI-based triple therapy and reinforcement of HCV screening and treatment access.

(Click on picture to enlarge)

screenShot
ABSTRACT

Background & Aims

The dynamics of hepatitis C virus (HCV) infection, as well as screening practices and access to therapy, vary among European countries. It is important to determine the magnitude of the effects of such differences on incidence and mortality of infection. We compared the dynamics of infection and screening and treatment practices among Belgium, France, Germany, Italy, Spain, and the United Kingdom. We also assessed the effects of treatment with pegylated interferon and additional effects of triple therapy with protease inhibitors.

Methods

We created a country-specific Markov model of HCV progression based on published epidemiologic data (on HCV prevalence, screening, genotype, alcohol consumption among patients, and treatments) and reports of competitive and hepatocellular carcinoma mortality for the 6 countries. The model was used to predict the incidence of HCV-related cirrhosis and its mortality until 2021 for each country.

Results

From 2002 to 2011, antiviral therapy reduced the cumulative incidence of cirrhosis by 7.1% and deaths by 3.4% overall. Reductions in incidence and mortality values ranged from 4.0% and 1.9%, respectively, in Italy to 16.3% and 9.0%, respectively, in France. From 2012 to 2021, antiviral treatment of patients with HCV genotype 1 infection that includes protease inhibitor-based triple therapy will reduce the cumulative incidence of cirrhosis by 17.7% and mortality by 9.7% overall. The smallest reduction is predicted for Italy (incidence reduced by 10.1% and mortality by 5.4%) and the highest is for France (reductions of 34.3% and 20.7%, respectively).

Conclusions

Although HCV infection is treated with the same therapies in different countries, the effects of the therapies on morbidity and mortality vary significantly. In addition to common guidelines that are based on virologic response-guided therapy, there is a need for public health policies based on population-guided therapy.

Knowledge of the natural history of hepatitis C virus (HCV) infection can help to develop models for predicting the future course of HCV infection.1, 2, 3, 4, 5, 6, 7 Accuracy of a predictive model of spread of HCV infection requires elucidation of the dynamics of infection, the epidemiologic pattern of contamination routes, and distribution of genotypes. These parameters vary between countries and must be evaluated by robust studies at a national level.

The impact on disease progression of HCV eradication via current antiviral therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) is well known.8, 9 Future therapeutic combinations using triple therapy of directly acting antivirals, namely protease inhibitors (PIs), with PEG-IFN and RBV should form the basis of treatment of naive10, 11, 12, 13, 14, 15 and experienced16, 17, 18 with HCV genotype 1 (G1) infection. However, no clinical studies have assessed the impact of antiviral therapy on long-term morbidity and mortality because it is unethical to maintain patients without therapy. Only a modeling approach can address this issue and predict its impact on a population.5

The development of country-specific models enables comparison of HCV natural history, prevalence according to fibrosis stage, and impact of therapy on HCV burden across countries. Recent studies pointed out substantial discrepancies in Europe in terms of HCV burden19 and access to antiviral therapy.20 Indeed, the prevalence of HCV ranged from 0.6% in Germany to 4% in Italy, and the number of patients treated ranged from 16% of HCV prevalent cases in France to 3% in Italy and the United Kingdom.19, 20 Until now, the impact on HCV morbidity and mortality of differences in access to treatment in different European countries has been ignored. A modeling approach taking into account national characteristics such as epidemiologic patterns, natural history, screening, and treatment rates may help to adapt therapeutic strategies and public health policies to the national HCV burden and "population-guided therapy."

In this study, we built country-specific models for Belgium, France, Germany, Italy, Spain, and the United Kingdom. Our main objectives were to (1) compare these countries in terms of dynamics of infection, natural history, screening, and treatment practices; (2) assess, by country, the impact of pegylated bitherapy; and (3) predict the additional impact of triple therapy with PIs.

Discussion

The dynamics of infection, natural history, screening, and therapeutic access are important components affecting progress in antiviral therapy in terms of morbidity and mortality. Taking into account these parameters, we show here that (1) the dynamics and natural history of HCV infection differ drastically in Belgium, France, Germany, Italy, Spain, and the United Kingdom; (2) the impact of antiviral therapy in reducing the incidence of cirrhosis and deaths substantially varies across these countries; (3) for G1 patients with HCV, the impact of PI-based triple therapy from 2012 to 2021 might vary from 10.1% to 34.3% for HCV-related cirrhosis and from 5.4% to 20.7% for HCV-related mortality; and (4) ideally, 75% of HCV screening by 2015 and one patient out of two treated in 2015 (with triple therapy for G1-infected patients and pegylated bitherapy for other genotypes) in all these countries would impact HCV morbidity and mortality from 2012 to 2021 (from 19.5% to 36.7% and 10.6% to 22.5%, respectively). The present study provides a new concept that could help in creating public health policies for population-guided therapy.

The present modeling study showed significant differences in the spread of HCV infection, leading to specific patterns of natural history in these European countries. Indeed, the total number of patients with cirrhosis (including complications) is expected to peak in 2020 for Belgium, 2021 for France, 2023 for Germany, 2030 for Spain, and 2033 for the United Kingdom in the absence of treatment; for Italy, the peak was reached in 2008. These differences in fibrosis stage distribution over time are related to patterns of HCV infection. Belgium, France, and Germany present patterns similar to that predicted by Davis et al in the United States.4 In Italy, an intensive epidemic wave appeared to have occurred during the 1950s and 1960s, mainly associated with poor hygiene during invasive procedures (eg, surgery, gynecology, dentistry, vaccinations, injection of antibiotics and vitamins), whereas in other countries the most intensive epidemic waves occurred during the 1980s, mainly related to transfusions and intravenous drug use. Consequently, in Italy, although antiviral therapy should reduce HCV morbidity and mortality, it will not affect the year or magnitude of the peak; in all other countries, antiviral therapy will have an impact on both (results not shown).

Our main concern was to develop country-specific models that fit "real-life" data integrating the probability of being treated based on clinicians' decisions and health policies. We used PEG-IFN sales obtained from GERS (for France) and IMS (for other countries). These data enabled us to estimate the annual likelihood of being treated among screened patients, and each country-specific model was calibrated according to the number of treated patients. These numbers are a consequence of the contraindications and side effects profile of the IFN-based regimen. Indeed, clinicians aware of the side effects profile of an IFN-based regimen adapt their decisions according to patient characteristics. For example, few patients aged 70 years in F0-F1 were treated in 2011 (from 0.8% in Italy to 4.0% in France; data not shown). Overall, estimated likelihoods depend on country, year, genotype, treatment history (naive vs re-treated patients), fibrosis (≥F2 vs F0-F1), and the presence of alcohol abuse. In addition, the proportion of prior nonresponders with F3-F4 in our model was based on clinical practice, which differs from licensing trials. Indeed, the proportion of F3-F4 among treated patients depended on the distribution of fibrosis among screened patients, which was the result of natural history modeling, the higher likelihood of treatment among F2-F4 patients, and the fact that naive F3-F4 patients had a lower probability of SVR and therefore higher probability of being nonresponders. The latter 2 points (higher likelihood of being treated and lower SVR probability) synergistically increment the proportion of prior nonresponders with F3-F4.

During the past decade (2002-2011), the overall reduction in morbidity and mortality was much higher in France (-16.3% and -9.0%, respectively) compared with other countries (ranging from -4.0% to -11.2% and -1.9% to -5.5%, respectively). Although the use of PIs in G1 patients will increase the impact of antiviral therapy on morbidity and mortality during the next decade (2012-2021), this study also underlines the urgent need for reinforcement of HCV screening and access to therapy. Indeed, the hypothetical scenario involving use of PIs with the same targeted level of HCV screening and access to therapy for all countries indicates that all countries except Italy will catch up with France. Moreover, sensitivity analysis assuming progress expected due to drugs currently in development clearly confirmed that any progress in SVR will mainly have an impact on HCV-related morbidity and mortality if accompanied by an increase in HCV screening and access to therapy. These data reveal the complex role of the spread and natural history of HCV infection and emphasize the need for innovative public health strategies in population-guided therapy. This approach of targeted public health strategies may also be useful for countries outside of Europe but will necessitate data for country-specific models.

Until now, experts have been focusing primarily on management of patients according to virologic kinetics and disease severity. The present study shows that, although clinicians from different countries use the same drugs according to therapeutic guidelines provided by scientific organizations, the impact on morbidity and mortality across countries varies as a result of differences in the spread of HCV infection, screening, and access to therapy. Therapeutic guidelines are first set up for patient care at an individual level but do not have the tools for measuring treatment impact on morbidity and mortality at a population level. This study suggests that delaying treatment in patients with F0 or F1 until they progress to F2 is efficient. However, this strategy is difficult in clinical practice because of the need for an efficient diagnostic method to detect fibrosis progression from F0-F1 to F2 as well as optimization of the interval and frequency of diagnostic testing specifically adapted to patient characteristics. Our results should be useful to national experts when proposing therapeutic guidelines.

As expected in a modeling approach, the present work had limitations associated with data and assumptions. Country-specific models were developed after identifying at least one expert in each country so as to obtain the most accurate analyses. Moreover, the country-specific data used to adjust or calibrate each model led to constraints that made certain assumptions impossible. However, one limitation concerns the assumption of the past incidence of HCV infections. We assumed that the past incidence of HCV infections decreased from 1990 at the same proportions as those observed in the United States, except for Italy and the United Kingdom. Indeed, the same assumption was first made for the United Kingdom, but it did not enable a good fit for reported HCC deaths related to HCV. This assumption seemed valid for countries in which transfusion-induced infections were predominant before 1990, but not for the United Kingdom, with infections mainly occurring in intravenous drug users. Moreover, in an earlier work performed in France, the impact on future morbidity and mortality of the variation in the decrease of the incidence of HCV after 1990 was found to be small.5 Secondly, we used data on PEG-IFN purchases in each country during 2002-2005 to calibrate our model. Limitations exist concerning our assumptions and parameters used to convert sales into patient figures. However, our strategy consisted of identifying experts possessing both PEG-IFN sales data and the expertise needed to convert these sales into numbers of treated patients.20 Thirdly, liver transplantation was not considered. Indeed, liver transplantation for HCV-related liver failure or HCC represents only a small number in comparison to HCV mortality. For example, in Spain, the country with the highest liver donation rate in Europe, 378 liver transplantations for HCV-related liver failure and HCC were performed in 2009, but there were 4500 HCV-related deaths. In addition, liver transplantation does not eradicate the disease, because patients are still at risk for disease progression and 5-year survival is approximately 65%.54, 55 Thus, liver transplantation should not significantly affect results.

In conclusion, the present study clearly shows the benefit of antiviral therapy in European countries, amplified by the use of PIs. The present data should help public health authorities to optimize the impact of such therapy on morbidity and mortality.

Results

HCV Natural History

Figure 1 shows the distribution of fibrosis stage over time using the no-treatment scenario for each country. Belgium, France, and Germany showed the same pattern of HCV natural history across fibrosis stages. For those countries, cases of cirrhosis and its complications, such as decompensated cirrhosis and HCC (F4 and its complications), would have stabilized around 2020-2024. In Spain and the United Kingdom, cases of cirrhosis and complications from the disease should continue to increase over the study period, reaching a peak in 2030 and 2033, respectively (not shown). In contrast, in Italy, due to a less recent HCV epidemic, cases of cirrhosis and complications would have already reached their peak of prevalence (2008 in the absence of treatment).

Impact of HCV Treatment on HCV-Related Cirrhosis and Mortality

Impact of pegylated bitherapy from 2002 to 2011

Table 1 shows the impact of treatment over the past 10 years (2002-2011), giving estimates of cumulative HCV-related cirrhosis and HCV-related deaths without and with treatment. Overall, HCV treatment reduced the cumulative incidence of cirrhosis from 414,400 (95% CI, 393,100-432,500) to 385,000 (95% CI, 365,600-401,200) (ie, -7.1%) during this period. The impact of treatment on reduction in HCV-related cirrhosis is shown in Figure 2A for each country; reduction varied from 4.0% in Italy to 16.3% in France. As expected, this reduction was higher for G2/3 (from 138,400 to 122,300 cases of cirrhosis; -11.6%) than for G1/4 (from 276,000 to 262,800 cases of cirrhosis; -4.8%). This difference was found for all countries (Figure 2A).

Similarly, HCV treatment reduced the cumulative incidence of deaths from 286,000 (95% CI, 273,400-298,000) to 276,400 (95% CI, 264,300-287,800) (ie, -3.4%) from 2002 to 2011. The weakest impact was obtained for Italy (-1.9%) and the strongest for France (-9.0%) (Figure 2B). Again, HCV treatment had a greater impact on G2/3 (from 93,000 to 87,400 deaths; -6.0%) than on G1/4 (from 193,000 to 188,900; -2.1%), and this difference was found for all countries (Figure 2B).

Future Impact of Antiviral Therapy Integrating Triple Therapy on G1 From 2012 to 2021
Overall impact on patients with HCV

Table 2 shows the impact of treatment over the next 10 years (2012-2021), with the cumulative incidence of HCV-related cirrhosis and HCV-related deaths predicted without and with treatment, including PI-based triple therapy for G1 (most conservative assumption, assuming no change in the evolution of screening rates or treatment practices for each country). Overall, HCV treatment would reduce the cumulative incidence of cirrhosis from 400,300 (95% CI, 378,300-412,600) to 318,100 (95% CI, 301,400-328,700) (ie, -20.5%) from 2012 to 2021 and the cumulative incidence of deaths from 316,200 (95% CI, 300,600-330,000) to 277,600 (95% CI, 264,200-289,200) (ie, -12.2%) from 2012 to 2021. Again, the lowest impact would be observed in Italy (12.9% and 7.5%, respectively) and the highest in France (38.9% and 25.5%, respectively) (not shown).

Specific Impact on G1 Patients With HCV

PI-based triple therapy would considerably impact the HCV-related incidence of cirrhosis in G1 patients, with relative impact varying from 10.1% (Italy) to 34.3% (France) and intermediate relative impacts of 11.7% in the United Kingdom, 15.8% in Belgium, 18.4% in Spain, and 24.0% in Germany (Figure 3A). The additional impact of PI-based triple therapy versus pegylated bitherapy would vary between 24% in Belgium and 44% in France (Figure 3A). Similarly, PI-based triple therapy would affect the HCV-related incidence of deaths for G1, with relative impact varying from 5.4% in Italy to 20.7% in France (Figure 3B). The additional impact of PI-based triple therapy versus pegylated bitherapy would vary from 21% in Belgium to 38% in France (Figure 3B).

If we now consider that the availability of triple therapy will be accompanied by reinforced screening and treatment access (less conservative assumption, assuming that 75% of HCV-infected patients will be screened by 2015 and one G1-infected patient out of two will be treated in 2015 with PI-based triple therapy), the overall relative impact of PI-based triple therapy on the HCV-related incidence of cirrhosis would be 27.4% (from 19.5% in Italy to 36.7% in France) (Figure 3A). Moreover, the additional impact of PI-based triple therapy versus pegylated bitherapy would be dramatically increased. Similarly, in the less conservative scenario, the relative overall impact of PI-based triple therapy on the HCV-related incidence of death would reach 15.0% (from 10.6% in Italy to 22.5% in France) (Figure 3B), and the additional impact of PI-based triple therapy versus pegylated would be dramatically increased.

Sensitivity Analyses

The scenario that consists of withholding treatment until reaching F2 is more efficient than the others ("Never treating patients with F0 or F1" or "Not treating patients with F0 or F1 until they reach F3"), as shown in Supplementary Table 6.

The future expected regimen (assumed to be available in 2017) would considerably impact the overall HCV-related incidence of cirrhosis and death from 2017 to 2026, with an even greater effect with reinforcement of HCV screening and treatment access (Figure 4A and B). Detailed results are shown in Supplementary Table 7.

Materials and Methods

Overview

We used a country-specific back-calculation method and a state-transition Markov model to first reconstruct the past incidence of HCV infection and simulate progression of HCV disease among newly HCV-infected cohorts in Belgium, France, Germany, Italy, Spain, and the United Kingdom. Next, we projected country-specific HCV-related morbidity and mortality and assessed the impact of therapy for each country.

Natural History of Disease in Newly HCV-Infected Cohorts

Newly HCV-infected cohorts were derived from country-specific past incidence of HCV infection, with the latter estimated during a back-calculation process. Past incidence of HCV infection was assumed to follow a logistic function until a peak of infection in 1989 for all countries except Italy. For Italy, where a more intense epidemic wave occurred during the 1950s to 1960s via iatrogenic transmission due to use of unsterilized material,21 the peak of infection was set at 1969. Past incidence of HCV infection was then assumed to decrease in the same proportions as those observed in the United States thereafter (94% decrease between 1989 and 2008),22 except for Italy and the United Kingdom. For Italy, we used the same decrease as that estimated by Mariano et al,21 that is, from a 21% decline in 1970 to a 98% decline in 2000. For the United Kingdom, where most HCV infections occurred in intravenous drug users, the decrease was assumed to be lower than in the United States,23 that is, a 46% decrease between 1989 and 1998 followed by stabilization.

Newly HCV-infected cohorts in each country were characterized by age at the time of HCV infection, sex, genotype (see Supplementary Table 1), and alcohol abuse status (T. Stroffolini, personnal communication, 2010, for Italian data).24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 The Markov model (see Supplementary Materials and Methods) used to simulate progression of these newly HCV-infected cohorts is detailed elsewhere.5 Death rates from causes other than HCV (competitive mortality) were assumed to be all-cause mortality from country-specific life tables.

Impact of HCV Treatment on Disease Progression

As previously determined, antiviral treatment effects were incorporated by estimating likelihood of being screened for HCV, of being treated, and of reaching sustained virologic response (SVR) after treatment according to the HCV genotype for naive and previously treated patients.

The likelihood of being screened for HCV differed between countries (see Supplementary Table 1). France was the only country for which we had 2 estimates of HCV screening: 24% in 1994 and 57% in 2004.38 As previously determined,5 we assumed a linear increase in HCV screening between 1994 and 2004 but assumed a lower increase in HCV screening thereafter so as to be at a 62% level in 2009. In Belgium, a study based on recall of patients after use of inactive batches of Cidex (Johnson & Johnson Medical, UK) disinfection solution in Belgian hospitals in 2000 estimated that 99 of the 265 (37%) positive patients already knew their status.39 For Germany, based on the work of Zehnter et al,40 we estimated that 40% of HCV-infected persons were screened in Germany in 2004, similar to data from a European report41 (see Supplementary Materials and Methods for details). In Italy, Mariano et al estimated that, among HCV RNA-positive individuals detected on screening, 40% already knew of their infection in 2005.21 For Spain, we extracted an HCV screening rate of 33% compatible with the estimate that 53% of HCV-related hepatocellular carcinomas (HCCs) were screened during 2008-2009 according to Varela et al42 (see Supplementary Materials and Methods for details). For the United Kingdom, we assumed an HCV screening rate of 30% in 2004 according to estimates of diagnosed populations found in national reports.43, 44 For those 5 countries, we assumed a linear increase in HCV screening starting at approximately 3% at the beginning of treatment (1991).

The likelihood of being treated for patients aware of their infection also differed between countries and was fitted to the 2002-2005 number of treated patients extracted from PEG-IFN sales obtained from GERS (http://www.gie-gers.fr/) for France and from the IMS (http://www.imshealth.com/portal/site/imshealth) for other countries (see Supplementary Materials and Methods).

The likelihood of attaining an SVR after treatment was obtained from the literature.8, 9, 10, 11, 13, 15, 17, 45, 46, 47

Procedure

During the process, the model was first fitted to reported age-specific annual HCC deaths related to HCV (see Supplementary Materials and Methods) in each country and calibrated to country-specific HCV prevalence and PEG-IFN sales in 2002-2005 (see Supplementary Table 1, Supplementary Table 2).

Next, the model simulated HCV progression until 2021 for all HCV infections occurring until 2010, assuming that current treatment practices with pegylated bitherapy would be continued until 2021. The model also simulated HCV progression until 2021 in the absence of treatment for each country. We then assessed the availability of triple therapy with PIs starting in 2012 and leading to a higher SVR for G1-infected patients, which was 78% in F0-F2 and 62% in F3-F4 naive patients and 66% in F0-F2 and 48% in F3-F4 non-naive patients after correction for proportions of relapsers and nonresponders from the IDEAL study.11, 18, 48 The 2 treatment regimens (pegylated bitherapy and triple therapy for G1-infected patients) were compared with absence of treatment.

The relative impact of treatment (either pegylated bitherapy or triple therapy) was calculated by subtracting the cumulative incidence (either HCV-related cirrhosis or HCV-related deaths) estimated with treatment from that estimated without treatment, divided by the estimated incidence without treatment. Because it is important that clinicians be able to assess the impact of triple therapy compared with pegylated bitherapy, the additional impact of triple therapy compared with pegylated bitherapy was estimated by subtracting the relative impact of triple therapy from that of pegylated bitherapy, divided by the relative impact of pegylated bitherapy. To assess the impact of triple therapy, we first held the assumption that HCV screening rates and treatment access would remain unchanged (most conservative assumption). In an alternative scenario, we assumed that HCV screening rates and treatment access would increase for each country with the availability of triple therapy, leading to 75% of HCV-screened patients by 2015 and one patient out of two treated in 2015 with new triple therapy for G1 and pegylated therapy for other genotypes (less conservative assumption).

The 95% confidence intervals (CIs) were calculated from the estimated variance-covariance matrix of the estimated parameters. We redid the entire country-specific analyses from these lower and upper bounds to obtain a 95% CI of HCV-related morbidity and mortality.

Sensitivity Analyses

Controversies persist as to whether patients in F0 or F1 need to be treated. The group of G2/3 patients with the highest SVR is best suited for testing a strategy of withholding patients in F0 or F1. Evaluation of such a strategy requires testing 3 potential treatment scenarios with PEG-IFN and RBV: (1) never treating patients with F0 or F1, although some of them will progress; (2) not treating patients with F0 or F1 until they reach fibrosis F2; and (3) not treating patients with F0 or F1 until they reach fibrosis F3.

Given the rapid pace of HCV drug development, we integrated future regimens into the 10-year horizon (2012-2021), considering the first 5 years with dual therapy of PEG-IFN and RBV (non-G1) or triple therapy (G1) and the next 5 years with an IFN-free regimen for G2/3 treatment-naive patients and triple or quadruple therapy for other patients. However, a realistic evaluation of the future regimen requires at least a 10-year period following the year of start of this therapy, leading us to provide results for 2017-2026. We based our assumptions on results of clinical studies evaluating future treatment regimens that are nearing phase 3 testing and will probably be available in the near future.49, 50, 51, 52, 53 To remain conservative, and because most studies recruited patients without extensive fibrosis, we applied a 20% reduction in efficacy for F3-F4 (see Supplementary Table 5). We first held the assumption that the HCV screening rate and treatment access would remain unchanged. To underline the urgent need for combining progress in the SVR rate with reinforcement of HCV screening and access to therapy, we performed the same scenario assuming that 75% of HCV-infected patients will be screened by 2017 and one infected patient out of two will be treated in 2017 with the future treatment regimen.

Additional sensitivity analyses were performed and can be found in the Supplementary Materials and Methods.

Source

Download the PDF here

Gastroenterology October 2012

JOHN W. WARD
Division of Viral Hepatitis
Centers for Disease Control and Prevention
Atlanta, Georgia

DAVID B. REIN
NORC at the University of Chicago
Chicago, Illinois

BRYCE D. SMITH
Division of Viral Hepatitis
Centers for Disease Control and Prevention
Atlanta, Georgia

"HCV morbidity and mortality are increasing, and these increases can be curbed by expanded access to HCV testing and a growing array of effective HCV therapies. This era of effective therapy for HCV creates opportunities for health leaders worldwide to identify and implement new strategies that increase the number of HCV-infected persons who are aware of their infection and who receive effective treatment.......potential impact of HCV therapy in curbing the expected increases in HCV-related cirrhosis and mortality......a greater payoff in disease averted and lives saved when improvements in HCV therapy are accompanied by expanded access to HCV testing, care, and treatment.........4 most recently published models of HCV disease in the United States, each of which demonstrates how the implementation of new testing strategies and/or treatments can cost-effectively diminish the accelerating public health impact of HCV infections acquired decades in the past.12, 13, 14, 15

from Jules of NATAP: in NYC we are now implemented in what I call the model for the "HCV Urban Plan", the HCV Ryan White Care Act". It is a $2 million 1-year demonstration project whose model includes a seamless 'soup to nuts' continuum of services required to address this epidemic in urban small & large cities in the USA or anywhere in the USA, whose model can be duplicated with changes based on local culture in any city globally. The model provides a total-city community inclusive response/mobilization including the Department of Health & community groups & care clinics. There are 6 major key program components: large-scale awareness project, rapid HCV testing, well defined & trained patient navigators, community-based & university clinics, support services for patients, clinics & project, and weekly web-based treatment & care education by a leading local & global hepatologist(s) for clinicians, which will expand treater pool. This project focuses on the most marginalized patient populations in inner city NY due to limited funding but can & should be expanded to all populations which can be accomplished with large scale awareness projects. I designed the original model & raised the funds, the NYC DOH is implementing the project with 8 test sites, 7 patient navigators, 6 community-based clinics. Two HCV databases are collecting medical & demographic data, which could lead to joined databases globally or throughout the USA if this project were duplicated, and multiple professional evaluations are being conducted. The key of this project is that it at-once mobilizes & creates an excitement for a city's community, both public & private, as it has in NYC. Separate isolated screening projects NOT joined together in one joint citywide project cannot accomplish this & will be self-defeating. The NYC project creates a safe environment for the most vulnerable patient populations, evaluations so far report this. Initial cuts of data collected are impressive.

Health leaders around the world are facing critical questions regarding how to combat a rising tide of hepatitis C virus (HCV)-associated liver disease. Worldwide, an estimated 130-170 million persons are living with chronic HCV infection, and HCV causes 1 in 4 cases of cirrhosis and 170,000 deaths per year.1 Persons living with HCV are often unaware they are infected, reflecting the relatively asymptomatic nature of HCV infection until late in the course of disease and the often decades-long latency between acquisition of HCV and the development of end-stage liver disease and death. Many HCV-infected persons were infected decades ago, before the discovery of the virus in the late 1980s and the advent of blood bank screening and other prevention measures. As time passes and HCV has a longer opportunity to cause progressive liver damage, the number of HCV-infected persons developing end-stage liver disease (hepatocellular carcinoma and liver cirrhosis) is increasing at an accelerating rate.2 For example, in the United States, the number of persons dying from HCV-associated conditions recently surpassed the number of deaths from HIV/AIDS. The US Centers for Disease Control and Prevention (CDC) estimate that HCV-related cirrhosis and morbidity will continue to increase year over year into the next decade and beyond.3, 4

Fortunately, health officials are not empty handed in facing this looming crisis. A growing arsenal of direct-acting antiviral agents can clear HCV from the body (ie, achieve virologic cure). The addition of 1 of 2 commercially available protease inhibitors to treatment regimens can increase rates of sustained virologic response (ie, viral eradication after completion of treatment) to 63%-75%.5, 6 Other compounds under study in clinical trials may increase rates of viral eradication even further.7 Achieving a sustained virologic response is important, because persons successfully clearing virus after HCV therapy have lower rates of hepatocellular carcinoma and all-cause mortality.8, 9

The opportunity created by these new therapies is compromised by the lack of quality information that can be used to target case identification and treatment efforts. Insufficient public health surveillance systems that track HCV disease, mortality, and access to testing and medical care hinder health leaders from recognizing the growing threat of chronic hepatitis C and the potential benefits that accompany HCV testing, care, and treatment.10 Seeking to fill this information gap, Deuffic-Burban et al brings together data from 6 European countries to model trends in HCV-related cirrhosis and mortality and to identify the potential impact of new HCV therapies on these trends.11

To estimate the country-specific impact of treatment on the incidence of cirrhosis and mortality for the 6 European nations over the past 10 years and in the 10 years to follow, the authors make several assumptions and use a complex simulation model. Despite its complexity, at the core, this model forecasts a future of increasing HCV morbidity and mortality for these countries while demonstrating the promise of enhanced HCV screening and new therapies in limiting the impact of HCV infection. The model in the Deuffic-Burban et al paper mirrors the 4 most recently published models of HCV disease in the United States, each of which demonstrates how the implementation of new testing strategies and/or treatments can cost-effectively diminish the accelerating public health impact of HCV infections acquired decades in the past.12, 13, 14, 15

Much of the complexity and assumptions of the Deuffic-Burban et al model were associated with the authors' objective to obtain country-specific estimates for each of the 6 nations. The authors found a range of possible impacts of HCV infection and new treatments over the coming decades, which varied based on differences in local epidemiology, HCV genotypes, and national health systems. Although the authors made a laudable effort to synthesize a wide range of data from a variety of sources, additional primary data on HCV are badly needed.

Several limitations are noted by the authors, including assumptions about past disease incidence, techniques to recreate treatment rates from pharmaceutical sales data, and the use of expert opinion in the place of observational data. These limitations point to a larger truth: When compared with other chronic, progressive diseases, there is much to be learned about HCV epidemiology, the rate of progression to end-stage liver disease, and the relative risk of liver cancer and liver failure depending on achievable sustained virologic response rates.

Despite these limitations, the authors' estimations provide data in ≥3 key areas. First, as with forecasts for the United States, all of these countries (with the exception of Italy) can expect increases in HCV-related cirrhosis into the next decade and, for Spain and the United Kingdom, likely beyond. For some countries, these trends signal a need for immediate action. In Belgium, France, and Germany, the epidemics of HCV-related disease are expected to peak within 10 years, leaving little time to expand capacity for HCV testing, care, and treatment.

Second, the Deuffic-Burban et al model also demonstrates the potential impact of HCV therapy in curbing the expected increases in HCV-related cirrhosis and mortality. Assuming no changes in screening or treatment practices in the next 10 years, the authors estimate HCV treatment-related reductions in cirrhosis and mortality by 21% and 12%, respectively. However, the projected declines were not uniform. For example, the authors forecast the greatest impact of HCV therapy for France (39% reduction in cirrhosis, 26% decreases in mortality), where the authors estimate a larger proportion of HCV-infected persons are tested and receive treatment.

Finally, the model of Deuffic-Burban et al also suggests a greater payoff in disease averted and lives saved when improvements in HCV therapy are accompanied by expanded access to HCV testing, care, and treatment. Although the data are sparse, the author's estimate that with the exception of France, ≤50% of HCV-infected persons have been tested. The authors demonstrate that increases in HCV testing and treatment could result in an additional 26% reduction in cirrhosis cases and 20% reduction in deaths averted among persons living with hepatitis C.

With the availability of effective HCV therapies, countries can use data and models, like those employed by Deuffic-Burban et al, to reconsider and realign their prevention priorities. In the United States, where an estimated 45%-85% of HCV-infected persons are unaware of their infection,16 national priorities for HCV prevention are being transformed to help identify HCV-infected persons and link them with care and treatment. Specifically, the CDC recently expanded its HCV testing guidelines to recommend a 1-time HCV test for all persons born in and between 1945 and 1965, reflecting the high HCV prevalence (5-fold greater than other adults in the United States), burden of HCV infection and mortality (approximately 75% of all HCV infections for both) among persons in this population.16 With full implementation of this strategy, CDC estimates that 800,000 persons currently unaware of their HCV infection will be identified. Moreover, when persons found to be HCV infected are linked to appropriate care and direct-acting antiviral agents treatment, >120,000 HCV-related deaths will be averted. With forecasted estimates and additional primary data points, other countries can examine their existing HCV testing policies and design new approaches tailored for their own epidemiologic characteristics of infection, resulting in greater reductions in HCV morbidity and mortality trends.

The health impact of expanded HCV testing can only be achieved when persons found to be infected with HCV receive appropriate care and treatment. Thus, regardless of country, policies must be accompanied by resources for a comprehensive set of implementation activities (eg, community education, provider training, laboratory quality assurance, and antiviral therapy). National plans can bring together different health sectors to improve HCV prevention by ensuring that more persons receive testing and recommended care and treatment services.17 Recognizing the need for such policies, the US Department of Health and Human Services published a viral hepatitis action plan in 2011 that outlines explicit steps for improving HCV testing, care, and treatment.18

The limitations in the Deuffic-Burban et al model highlight the need for better primary data to inform decision making for health policies to prevent HCV and reduce HCV-associated morbidity and mortality. Despite these limitations, the trends identified by the authors underscore the powerful call to action needed to mitigate the harm of HCV infection: HCV morbidity and mortality are increasing, and these increases can be curbed by expanded access to HCV testing and a growing array of effective HCV therapies. This era of effective therapy for HCV creates opportunities for health leaders worldwide to identify and implement new strategies that increase the number of HCV-infected persons who are aware of their infection and who receive effective treatment. Further, with the collection of more robust primary data, countries can employ strategies reflective of their local epidemiology and feasible for their health systems. By implementing these changes, countries can achieve population-wide reductions in HCV-associated morbidity and mortality.

Source