Study Finds Too Few With Hepatitis C Start or Stick With Treatment

Interferon injections don't always work, but new therapies on the way, experts say

Wednesday, November 6, 2013

EDNESDAY, Nov. 6 (HealthDay News) -- A new study suggests that only a quarter of people with hepatitis C are willing to start the standard treatment for the serious viral infection.

When interferon injections -- the current standard treatment -- work, which only happens about 16 percent of the time, the risk of dying drops by 45 percent, the University of Southern California researchers said. Unfortunately, the drug doesn't always manage to suppress the virus completely and many people can't tolerate its side effects, which include gastrointestinal problems and anemia.

"This study points out the inadequacies of old therapies for hepatitis C," said Dr. Douglas Dieterich, a professor of medicine and liver diseases at the Icahn School of Medicine at Mount Sinai Hospital in New York City.

Hepatitis C is a viral infection that causes inflammation of the liver. It's transmitted from person to person via blood.

Liver specialists said that although this study may be reflective of what's currently going on in hepatitis C treatment, soon there will be a huge shift in the way the disease is treated.

"There's a revolution afoot in the treatment of hepatitis C," Dieterich said. He said new treatments that are taken in pill form should be approved in the coming months, and the newer medications will be far more effective at treating hepatitis C than interferon. He added that the treatment times also will be shorter.

"By the fourth quarter of next year, we'll have at least two new drug cocktails, curing upwards of 90 percent of patients -- even those with cirrhosis," he said.

Dr. David Bernstein, chief of the division of hepatology at North Shore University Hospital in Manhasset, N.Y., said the new treatment options are "exciting, but we need to remain somewhat skeptical because many of the studies were done on small groups."

Most people who have hepatitis C don't have any symptoms, and can go years without knowing they have the virus.

"The bulk of people with hepatitis C were born between 1945 and 1965, and more than three-quarters of those infected don't know they have it," said Dr. Paul Gaglio, medical director of the Montefiore Einstein Center for Transplantation, in New York City.

The current study included more than 360,000 U.S. military veterans who'd been diagnosed with hepatitis C. Ninety-seven percent were male, and their average age was 52. More than half were white and almost one-third were black.

Only 24 percent of the veterans chose to receive treatment for their hepatitis C. Of those who received treatment, just 16.4 percent achieved undetectable levels of the virus in their blood. That likely means that many of the study volunteers may have stopped taking the medication before the recommended 48 weeks of treatment was finished, Bernstein said.

The good news was that when the treatment did work, the risk of dying from any cause dropped by 45 percent.

"This study is indicative of standard practice now," Gaglio said. "Patients don't want to take the treatment because there are lots of side effects. But big changes are coming."

Bernstein said three new treatment regimens likely will be approved by the U.S. Food and Drug Administration in December, and another round of approvals likely will occur in late 2014 or early 2015.

All three experts said the message for people with hepatitis C is to go back to their doctor and get re-evaluated. New treatment options will soon be available, and they'll be available for folks with kidney disease and cirrhosis of the liver.

"The treatment world is really changing," Bernstein said.

Gaglio added that if you were born between 1945 and 1965 and you haven't been tested for hepatitis C, it's important to get tested to ensure that you aren't infected with the virus.

The study was published online Nov. 5 in the journal JAMA Internal Medicine.

SOURCES: Paul Gaglio, M.D., professor, clinical medicine, Albert Einstein College of Medicine, and medical director, Montefiore Einstein Center for Transplantation, New York City; Douglas Dieterich, M.D., professor, medicine and liver diseases, Icahn School of Medicine, Mount Sinai Hospital, New York City; David Bernstein, M.D., chief, division of hepatology, North Shore University Hospital, Manhasset, N.Y.; Nov. 5, 2013, JAMA Internal Medicine, online

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Pakistan asked to declare hepatitis emergency

Friday, November 08, 2013

By Imran Ali Teepu

WASHINGTON: On the sidelines of the American Association of Liver Disease (AASLD) conference, a number of international researchers and physicians asserted on Pakistan’s health officials to declare hepatitis emergency in country as over 9.4 million hepatitis-C patients suffers from the deadly disease.

\The AASLD concluded here in downtown DC the other day. At the concluding session the physicians specially took interest in the launch of two drugs – Sofusbivir and Simeprevir.

The two new treatments for hepatitis C are to be released in December 2013. Both the drugs extremely promising but the obstacles to their use in Pakistan and other developing countries would be their cost.

Talking to Daily Times Dr Abdul Nadir, internist/geriatrician in Phoenix, said that the cost of the two new agents, Sofusbivir and Simeprevir, for complete course of treatment of one patient has been estimated at over $ 60,000, clearly beyond the reach of even more fortunate Pakistani citizens.

However, he said: “The most common genotype of hepatitis C in Pakistan is III and one poster presented in AASLD reported that 60 percent to 90percent of patients achieved cure for HCV-genotype III (genetic structure of hepatitis C virus) after completing a 24-week course of Sofusbivir based oral treatment.”

He said that treatment does not require the use of interferon injections and thus has very few side effects and no resistance to the virus was identified either.

The outcome of treatment was best for those with milder form of liver disease compared to those who had advanced liver disease called cirrhosis.

He added that the basic ingredients of new HCV medications can be made quite simply and Pakistani scientists are capable to manufacture affordable, new and extremely potent HCV medications for their public.

Dr Andrew Hill, a PhD and a researcher based at the Pharmacology Research Lab Liverpool, United Kingdom told Daily Time, “Most of the hepatitis C patients almost 9.4 million are from low and middle class earning groups as per a research.”

He said that either Pakistan health authorities can negotiate an affordable price for the oral HCV medications or if that is not possible, Pakistan can declare a hepatitis emergency and start making these medicines through there own pharmaceutical industry.

According to data shared by researchers at the conference Human Immunodeficiency Virus (HIV) treatment was made available to general public in India and Brazil by making locally manufactured HIV drugs to their population.

It is worth noting that Pakistan’s federal government has almost abolished its Liver Transplant Centre established in Pakistan Institute of Medical Sciences and has done little on the internal medicine side.

The transplant centre was established with a cost of Rs200 million during the tenure of former prime minister Yousaf Raza Gilani and opened in June 2011. But within one year’s time soon after failure of first liver transplant in 2012, the centre was closed which highlighted bad public health planning on part of the federal government.

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Are metabolic factors still important in the era of direct antiviral agents in patients with chronic hepatitis C?

World J Gastroenterol. 2013 November 7; 19(41): 6947-6956.

Published online 2013 November 7. doi: 10.3748/wjg.v19.i41.6947.

Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.

Alessandro Grasso, Federica Malfatti and Roberto Testa.

Alessandro Grasso, Federica Malfatti, Roberto Testa, Gastroenterology Unit, Department of Internal Medicine, San Paolo Hospital, 17100 Savona, Italy

Author contributions: Grasso A collected the data and wrote the manuscript; Malfatti F critically revised the manuscript and contributed to the manuscript writing; and Testa R supervised the manuscript; all authors approved the final version of the manuscript.

Correspondence to: Alessandro Grasso, MD, Gastroenterology Unit, Department of Internal Medicine, San Paolo Hospital, Via Genova 38, 17100 Savona, Italy. a.grasso@asl2.liguria.it

Telephone: +39-19-8404280 Fax: +39-19-8404364

Received June 28, 2013; Revised July 27, 2013; Accepted August 16, 2013;

Abstract

The high rate of sustained viral response (SVR) to boceprevir or telaprevir-based triple therapy in hepatitis C (HCV)-related, non-cirrhotic naïve patients or relapsers to previous antiviral treatment leads clinicians to believe that the impact of metabolic host factors on SVR is minimal when triple therapy is used, unlike what is observed with the peginterferon and ribavirin schedules. This concept is strongly expressed by some opinion leaders on the basis of the data derived from sub-analyses of registrative trials as well as from a post-hoc analysis of the phase II C208 clinical trial. The perception of unrestrainable therapeutic success with the use of newer, more powerful antivirals is now reinforced by the brilliant results obtained with sofosbuvir, an HCV NS5B polymerase inhibitor, as well as by the data from the phase II and III studies on the various combinations of second-generation NS3/4A inhibitors and NS5A and/or NS5B inhibitors. However, a great deal of concern has emerged from the real world scenario in which patients are often older and have more comorbidities than patients in the “world of trials”. Furthermore, many of them have advanced fibrosis and previous failure with peginterferon and ribavirin treatment. Some data from the recent literature suggest that the host metabolic factors may play a minor but non-negligible role in these difficult-to-treat patients, an issue that will hopefully be investigated in further studies. This editorial aims to provide a detailed analysis of the role that host metabolic factors played in the past and what role they may play in the era of direct antiviral agents.

Keywords: Metabolic factors, Insulin resistance, Direct antiviral agents, Chronic hepatitis C

Core tip: This editorial explores the past and present role of metabolic factors by analyzing the data that has emerged from the post hoc analysis of registrative trials of direct antiviral-based treatment. Low-density lipoprotein-cholesterol and statin use proved to be predictors of sustained viral response (SVR) in both boceprevir and telaprevir-treated patients, respectively. Furthermore, HOMA-IR negatively influenced SVR in prior partial and null responders treated with telaprevir-based schedules. By transferring these data to the real world scenario in which patients have comorbidities, advanced fibrosis and prior failure to antiviral treatment, we believe that metabolic factors might play a non-negligible role in influencing antiviral response, even in triple therapy.

INTRODUCTION

More than 170 million people are chronically infected with the hepatitis C virus (HCV) worldwide[¹], thus HCV has become the main cause of chronic liver disease leading to death from liver failure or hepatocellular carcinoma (HCC) in many Western countries and in Japan[²]. Viral eradication resulting from antiviral treatment has led to a decrease in these complications. However, treatment with pegylated interferon and ribavirin, which has been the standard-of-care therapy for chronic hepatitis C for the last decade, has been able to cure only about 40%-50% of patients with hepatitis C genotype 1, the main strain in Europe and the United States[^3-6].

Genotype 1 is the main viral-related variable associated with treatment failure[^3,4]. However, a number of other pretreatment variables related to the virus (high viral load) and to the host (interleukin 28b polymorphism, age, overweight, metabolic factors), as well as on-treatment variables (4-wk negativization of viral load) have been shown to affect the response to anti-viral dual therapy[^7-10].

HCV INFECTION AND METABOLIC SEQUELAE: WHAT WE LEARNED FROM THE PAST

Insulin resistance

Epidemiological data suggest that HCV interferes with glucose and lipid metabolism. Patients with diabetes show a greater prevalence of HCV as compared to the non-diabetic population[¹¹]. Moreover, the prevalence of diabetes is significantly higher in chronic hepatitis C patients than in those with chronic liver disease other than HCV[¹²]. Furthermore, it is well known that HCV infection is an independent risk factor for developing diabetes[¹³]. These data suggest that HCV, rather than liver disease per se, predisposes patients to diabetes. The link between HCV and diabetes is the development of insulin resistance (IR), a metabolic prerogative of HCV (i.e., IR is more than six fold higher in HCV patients than in those with HBV)[¹⁴]. IR, hepatic steatosis and body mass index (BMI) are related in a genotype-dependent fashion. In fact, HCV genotype 3 exerts a direct cytopathic and steatogenic effect on hepatocytes, thus resulting in a higher prevalence of steatosis and a lower prevalence of IR compared with HCV genotype 1, which very quickly induces IR and some steatosis[^15-17]. IR occurs very early in transgenic mice expressing the HCV core protein and may even precede the occurrence of hepatic steatosis, thus indicating that IR is not a consequence of hepatic steatosis[¹⁸], similarly to what is observed in humans[¹⁷]. Furthermore, IR is a pro fibro genetic stimulus[¹⁷], thus patients with high IR show more advanced liver fibrosis than patients with low IR[¹⁹]. Finally, the association between IR and high HCV RNA levels[¹⁴] suggests a complex interplay between viral replication and insulin action. HCV may induce over-expression of the suppressor of the cytokine signaling-3 (SOCS3) gene in liver tissue. This gene is involved in the interferon signaling pathway and is associated with poorer treatment outcome[^20,21]. HCV core-induced SOCS3 may promote proteosomal degradation of the insulin receptor substrates 1 and 2 (IRS1/2), thus inducing severe hepatic IR[^22,23]. Both SOCS3 over-expression and hepatic steatosis promote intra-hepatic and systemic lipid oxidation, thus leading to an imbalance of total glucose disposal in the muscles and resulting in peripheral (and not only hepatic) IR[²⁴].

Direct involvement of HCV in glucose metabolism has also been demonstrated “in vivo”. In fact, there is robust evidence showing that IR improved significantly in patients with HCV genotype 1 who achieved SVR compared with patients who did not obtain viral clearance after treatment[^25,26]. Furthermore, achieving viral clearance is demonstrated to significantly reduce the risk of both type 2 diabetes in retrospective cohorts[²⁷] and of de novo IR in non-diabetic HCV patients[²⁸].

Lipids

Hepatic steatosis is also related, in a genotype-specific manner[²⁹], to a decrease in serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB), thus demonstrating the close link between HCV and lipids. A variable fraction of HCV in the serum circulates in lipo viro particles (LVP), with very-low-density-lipoprotein (VLDL) containing apoB and apoE. LVP reach the highest levels in the post prandial phase, suggesting that their formation is a dynamic process[³⁰]. Very recently, a strong correlation between the maximum amount of LVP in vivo and both IR and metabolic syndrome was reported, suggesting that lipids may play a role in HCV-induced IR[³¹]. ApoE is considered the central component of the HCV-host lipid interaction, mediating HCV infectivity via lipoprotein receptors[³²]. Lipoproteins (LP) are easily endocytosed, thus supporting the hypothesis that HCV can use this association with LP to adhere to the cell and subsequently enter the host cell by endocytosis[³³]. Various cell surface receptors, including tetraspanin CD814, scavenger receptor class B member I, tight-junction proteins claudin-1 and occludin, and clathrin-mediated endocytosis have been proposed as entry factors for HCV, but the role each of them plays remains controversial. Recently, the Niemann-Pick type C1-like 1 (NPC1L1) gene receptor has come to the attention of researchers in the view of a potentially new therapeutic antiviral strategy since it is the possible target of the receptor-blocker drug ezetimibe[^34,35].

Few and inconsistent data have been reported on serum lipid level modifications during interferon therapy. Increased total cholesterol and triglyceride levels have been observed with interferon treatment, with a subsequent drop to pretreatment levels of both after discontinuing therapy, but with different trends depending on the HCV genotype[^36,37]. In a small population of patients with genotype 2 and 3, viral clearance induced serum level modifications of lanosterol, a cholesterol precursor, suggesting a direct viral interference with the enzymes of sterol synthesis[²⁹].

The effects of IR on antiviral response to dual treatment

Patients with high IR show a slower decay of HCV viral load than patients with low IR, even in the very early phase of treatment (first 24 h), suggesting that hyperinsulinemia reduces the cellular response to pegylated-interferon[³⁸]. Furthermore, high IR has been associated with a low rate of rapid viral response (RVR) in genotypes 1[³⁹], 3[⁴⁰] and 4[⁴¹].

Whether or not IR influences SVR rate has been a question of debate since 2005[⁹]. Two meta-analyses assessing the impact of IR on treatment outcome, both of which included fourteen studies with more than 2700 patients, were published in 2011[^42,43]. However, among the studies which failed to find an association between IR and SVR, the main baseline HOMA value, an indirect measurement of IR[^44,45], was < 3 and the prevalence of advanced fibrosis or cirrhosis was also low or even absent[⁴²]. This observation supports the hypothesis that the HOMA value is predictive of response to antiviral treatment mainly in patients with advanced disease stage. Liver fibrosis is an event which may occur as a consequence of HCV-related chronic necroinflammatory activity or via HCV related IR, or probably both. However, non-HCV related IR (genetic, or related to true metabolic syndrome) may also occur since almost 25% of the general population has the metabolic syndrome stigmata[⁴⁶]. On the basis of these data, we can assume that a proportion of patients with prevalent virus-related IR (likely those with lower fibrosis as well as a lower incidence of cardio-metabolic comorbidities) have lower HOMA values and a higher likelihood of SVR after antiviral treatment, whereas other HCV patients with prevalent metabolic IR (likely those with the phenotype of metabolic syndrome) have a higher probability of advanced fibrosis as well as higher HOMA levels and a lower probability of achieving SVR[^28,42,47].

The effects of obesity and lipids on antiviral response to dual treatment

Obesity is another important metabolic cofactor that can affect antiviral response. It may induce IR and hepatic steatosis, both of which are associated with poor antiviral response either directly or by ultimately promoting liver fibrosis. However, it has been demonstrated that obesity is an independent negative predictor of response to antiviral treatment regardless of genotype and cirrhosis[⁷].

Obesity is now considered an inflammatory condition, resulting in an abnormal immune response to therapy. Adipose tissue secretes many proteins, including adipokines, which regulate hepatic and peripheral glucose and lipid metabolism. One of the adipokines secreted by adipose cells is leptin, whose expression is regulated by interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α) and insulin. Although leptin secretion from adipocytes provides antiobesity signals, obese patients have elevated levels of leptin. This suggests an intrinsic leptin resistance in the obese, a complex phenomenon involving increased levels of SOCS3, which impairs post-receptor signaling and leads to reduced adenosine monophosphate-activated protein kinase (AMPK) activation[^48,49].

Increased SOCS3 expression, which is associated with nonresponse to antiviral treatment[²⁰], has been demonstrated to be independently associated with obesity in patients with chronic HCV viral genotype 1[⁵⁰].

Regarding the role of circulating lipid levels on the efficacy of antiviral treatment, there are few, but concordant, data. Higher pretreatment total cholesterol and LDL-C[^51,52], as well as lower triglyceride levels are independent variables associated with higher SVR rates[⁵³].

The interplay of Interleukin 28b polymorphisms and metabolic variables

The relationship between IL28b polymorphisms and metabolic variables has been reported in several studies, thus emerging as a new and challenging issue. There is a close association between IL28b and lipid levels. In HCV genotype 1 patients, low apoE levels and higher LDL-C were associated with IL28b rs12979860 CC rather than CT/TT[^54,55]. Both IL28CC and LDL-C were good predictors of SVR, but the predictive power of IL28CC was higher. Thus, the LDL-C level was found to be a significant predictor of SVR, mainly for IL28 heterozygous CT patients[⁵⁶].

Furthermore, lower steatosis[⁵⁷] as well as lower IR[⁵⁸] have been seen in genotype 1 patients with IL28b rs12979860 CC. In a recent, large cohort of genotype 1 patients from Italy, IL28b rs12979860 CC was associated with higher levels of total and LDL-C, lower levels of triglycerides, lower prevalence of IR and moderate-to-severe steatosis. However, only IR and steatosis were associated with IL28b rs12979860 CC after correcting for BMI and lipid profile, suggesting an indirect role of LDL-C status on IL28b polymorphism[⁵⁸]. IR was found to have a predictive power for SVR which is independent of IL28 genotype[⁵⁹], although the likelihood of achieving SVR progressively increases from the lowest probability in patients carrying both negative predictors (IR and rs12979860 TT/TC; SVR = 20.7%) to the highest probability in patients with no IR and rs12979860 CC (SVR = 78.4%)[⁵⁸]. These data give rise once again to the thorny question concerning the intimate pathogenetic interplay between metabolic and genetic host factors.

Can pretreatment correction of the metabolic co-factor improve SVR to dual treatment?

One of the most intriguing and challenging tasks was to transfer the information regarding the predictive power of a metabolic variable for SVR to a practical ground. This gave rise to a series of studies aimed at improving SVR by correcting the metabolic factors before or during antiviral treatment.

Some studies with very small cohorts have explored the effect of a lifestyle intervention in obese and insulin-resistant subjects with chronic hepatitis C. BMI, HOMA values and leptin levels, but not TNF-α and IL-6, decreased significantly after aerobic exercise[⁶⁰]. A more structured intervention based on 24-wk dietary and physical activity regimens significantly reduced BMI and HOMA values[⁶¹] and could be an interesting baseline strategy in difficult-to-treat chronic hepatitis C patients who are obese and insulin-resistant prior to starting peginterferon and ribavirin. However, to date, no studies have demonstrated the efficacy of this strategy. Tarantino et al[⁶²] demonstrated that a low-calorie diet for 3 mo before starting antiviral therapy in patients with genotype 1-chronic hepatitis C resulted in a significant improvement in IR as well as a 60% “end-of-treatment” response rate in the low-calorie diet group as compared to the control group (17.6%).

More data have been reported on insulin sensitizing agents used in combination with peginterferon and ribavirin. The randomized, double-blind TRIC-1 trial by Romero-Gómez et al[⁶³] analyzed 125 naive genotype 1 patients treated with peginterferon alpha-2a and ribavirin plus metformin or placebo on an intention-to-treat basis. Their final results showed that there was a significant decrease in both HOMA value and viral load during the first 12 wk, as well as an improvement in SVR rate in the metformin group as compared with the placebo group, but only in females[⁶³]. While metformin failed to improve overall SVR, conflicting results have been obtained with other insulin sensitizing agents, mainly pioglitazone. Although comforting results have been obtained in genotype 4[⁶⁴], no improvement in SVR was observed by adding pioglitazone (30 mg/d) to peginterferon and ribavirin as compared with the standard of care of dual therapy[^65,66]. Similar negative results have been shown by Harrison et al[⁶⁷] in a randomized controlled trial which compared pioglitazone plus standard of care vs standard of care alone. This study definitively demonstrated that even when pioglitazone was administered at an appropriate dose (45 mg/d), it failed to improve SVR, regardless of administration timing (i.e., prior to starting the standard of care or during the peginterferon and ribavirin course)[⁶⁷].

ADVENT OF DIRECT ANTIVIRAL AGENTS AND THE NEW SCENARIO

In recent years, several antiviral drugs that directly target HCV have been developed. These new drugs, known as direct-acting antiviral agents (DAAs), are designed to interfere directly with the HCV life cycle by inhibiting enzymes such as HCV NS3/4A protease and HCV NS5B polymerase, or other proteins such as NS5A. Two NS3/4A protease inhibitors, boceprevir and telaprevir, have become the first new drugs approved for the treatment of patients with genotype 1 HCV who have either not previously received treatment or who failed to achieve SVR with previous therapy[⁶⁸]. These new drugs, however, must be given with peginterferon and ribavirin because of their low barrier to viral resistance when they are used as monotherapy, and this may limit efficacy. A further limitation is due to overall side effects resulting in higher discontinuation rates. However, when candidates for this treatment are carefully selected, the overall SVR rates can almost double in naïve and even triple in relapsers to previous double therapy[^69-75]. Thus, triple therapy is the new standard treatment for HCV genotype 1 chronic liver disease.

One of the questions under debate is whether the predictors of treatment failure that are observed when using dual therapy in HCV genotype 1 also exert a negative influence in triple therapy.

What we know about metabolic factors and triple therapy

Among the variables which have shown predictive power for SVR in dual therapy, some of them, such as IL28b polymorphism, fibrosis and the 4-wk viral response in both naive or previously treated patients, have also been highlighted in triple therapy on the basis of data emerging from registrative trials. Metabolic factors seem to play either no role at all, or only a minor one in influencing SVR in the context of triple treatment. However, some considerations have to be made when looking carefully at the post-hoc analysis of landmark phase-III trials.

In the boceprevir-based SPRINT-2 trial, two metabolic variables were associated with SVR, but only statin use proved to be an independent predictor of SVR (OR = 3.4; 95%CI: 1.1-10.7; P = 0.04), whereas BMI was not retained in the multivariate model after adjustment for other variables[⁷²].

In RESPOND-2, a boceprevir-based trial focusing on previously treated patients, both the response-guided treatment (RGT) group and the 48-wk triple treatment group had a significantly higher SVR rate compared with dual treatment. However, in obese patients (BMI ≥ 30), a 10% lower SVR rate was observed in the RGT group compared with the 48-wk triple treatment group (56% vs 65%)[⁷³].

A sub-analysis of baseline predictors in the SPRINT-2 and RESPOND-2 trials showed that a BMI ≤ 30 was significantly associated with SVR and with a ≥ 1 log10 HCV-RNA decline at week 4 in untreated patients but not in patients previously treated with peginterferon and ribavirin[⁷⁶].

In the two telaprevir-based studies carried out on untreated patients, both ADVANCE[⁷⁷] and ILLUMINATE[⁷⁵] showed a higher SVR rate in the RGT arms compared with the double treatment arm, regardless of diabetes and obesity. In the ADVANCE study, although a 30% greater improvement in the SVR rate of patients receiving telaprevir for 12 wk was achieved in all 3 BMI groups (< 25, 25-30 and > 30) as compared to the control group, a 12%-16% lower SVR rate was observed in overweight and obese patients compared to normal weight patients.

An important contribution was provided by Serfaty et al[⁷⁸] in their post-hoc analysis of the phase II C208 clinical trial[⁷⁹]. In this study, which is the first to focus on the influence of baseline metabolic variables on SVR in patients treated with triple therapy, only LDL-C was associated with SVR (even in multivariate analysis), thus confirming its predictive role for SVR even in the telaprevir-based triple regimen and not only in dual therapy. However, this is not the case for baseline IR measured by the HOMA index, which did not show any relationship with SVR. Furthermore, the HOMA index did not influence the 4-wk HCV RNA decline, nor were the rates of HCV RNA undetectability at week 4 found to differ among patients with or without IR. However, this is not surprising since baseline HOMA values were not found to be associated with SVR in many European studies in which the study population had a low prevalence of advanced fibrosis and a relatively low BMI[^39,40,80,81]. This may suggest that a higher prevalence of “viral” IR, which can easily be counteracted by antivirals, actually does exist in this population of patients. The significant association between HCV RNA and HOMA values in the study of Serfaty et al[⁷⁸], as well as the improvement of HOMA in patients who achieved SVR compared with those who did not, further confirm the direct “in vivo” involvement of HCV in IR pathways. On the other hand, a powerful, combined effect on suppressing HCV viremia and rapidly lowering IR was previously observed using a 14-d course of danoprevir monotherapy, i.e., another powerful, selective inhibitor of NS3/4A HCV serine protease. Interestingly, overweight patients had a greater decrease in HOMA values than patients with normal BMI, despite a similar decrease in serum HCV RNA, suggesting a complex interplay between these two variables. The authors hypothesize an anti-inflammatory or insulin sensitizing effect of danoprevir[⁸²].

Other important data concerning IR were obtained from a post-hoc analysis of the REALIZE phase III study which was carried out to assess the impact of IR on virological response to a telaprevir-based regimen in previously treated patients. Baseline HOMA values were found to be associated with SVR at univariate analysis (TVR: OR = 0.76; 95%CI: 0.60-0.96) but not after adjustment for other baseline prognostic factors (TVR: OR = 0.95; 95%CI: 0.71-1.29)[⁸³]. SVR decreased as HOMA values increased, both in the control group and in the pooled T12-PR48 group where, however, this trend was observed only in prior partial and null responders, but not in prior relapsers.

In summary, on the basis of all these data we can say that LDL-C and statin use proved to be predictors of SVR in telaprevir and boceprevir-treated patients, respectively. Obesity may negatively influence rapid virologic decline as well as SVR in previously naive patients treated with a boceprevir-based regimen. To the best of our knowledge, no sub-analysis regarding the impact of obesity on SVR has ever been carried out for telaprevir. No data on HOMA are available for boceprevir. HOMA values were reported as being univariately associated with SVR in a telaprevir-based trial on previously treated patients. In naive patients treated with a telaprevir-based regimen, the HOMA value was not a predictor of SVR, nor was it found to be associated with rapid virological response.

However, some comments have to be made. First, we have no data on the real weight of baseline metabolic factors in patients with less favorable probability of response, such as those with advanced fibrosis and/or non-CC IL28b. It is reasonable to suppose that in patients with advanced fibrosis or cirrhosis, as well as in prior partial or null responders to dual therapy and in whom non-CC IL28b is highly prevalent, metabolic IR, metabolic syndrome and obesity may be significant cofactors of nonresponse to triple therapy. Hopefully, this will be an issue for further studies. Secondly, in a real world setting we have to face a change in the epidemiology of candidates to triple therapy compared with the “world of trials”. In the “real world scenario” we have to expect a higher prevalence of patients over 65 years of age who have often previously been treated with dual therapy and have a higher prevalence of comorbidities, including hypertension, dyslipidemia and diabetes. In this context, many patients might experience either a worsening in the sensitivity to interferon as well as a higher probability of side effects when a protease-inhibitor is added to therapy.

These points seem to have been taken into consideration by United Kingdom consensus guidelines for the use of protease inhibitors in the treatment of HCV genotype 1 infected patients. These guidelines recommend evaluating the presence of factors predictive of poor response to therapy, such as BMI and type 2 diabetes among others[⁸⁴].

Currently, an enormous effort is being made by researchers and companies to provide physicians with new and more powerful drugs with a high genetic barrier and able to work on several HCV genotypes. Recently, phase II and III studies on sofosbuvir, a new nucleotide analogue HCV NS5B polymerase inhibitor used in combination with peginterferon and ribavirin in genotypes 1, 4, 5 and 6 or in combination with ribavirin in genotypes 2 and 3, showed a high rate of SVR, up to 90% in untreated genotype 1 patients after a 12-wk regimen, with no additional side effects to those occurring with peginterferon and ribavirin[^85-87].

New combinations of drugs with interferon-free schedules are under evaluation in phase II or III studies[^88-91]. Hopefully, by the end of the decade the holy grail of a pangenotypic oral association of highly powerful drugs will be able to cure virtually all patients. In this scenario, the role of predictors of SVR will rapidly fade, but we have to keep in mind that in the short amount of time that separates us from the availability of new and more powerful treatment schedules, many patients will have to be treated with boceprevir and telaprevir-based triple therapy. Furthermore, many patients around the world have no, or only limited access to DAAs. With this in mind, SVR predictors remain important tools that are available to us in order to assign patients to the best treatment schedules.

CONCLUSION

Baseline metabolic factors seem to have a minor, though likely not negligible, role in influencing antiviral response to direct antiviral agent-based treatment in patients with genotype 1 chronic hepatitis C. Further studies aimed at clarifying their role in a subpopulation of unfavorable candidates to this treatment, such as patients with advanced fibrosis or prior partial or null responders to peginterferon and ribavirin, are needed.

Footnotes

P- Reviewer: Pavlidis C S- Editor: Song XX L- Editor: O’Neill M E- Editor: Ma S

REFERENCES

Source

Bristol-Myers Squibb Evolves R&D Strategy

November 07, 2013

Bristol-Myers Squibb is evolving its strategic focus in R&D to ensure continued leadership in delivering innovative medicines for patients with serious disease. The company will focus investment on priority areas such as immuno-oncology, delivering its late-stage pipeline across all its therapeutic areas and focusing discovery to explore disease areas of highest unmet medical need where the company can bring the greatest value. The evolved strategic focus in R&D will support and advance Bristol-Myers Squibb’s overall BioPharma strategy, which remains unchanged.

“We are focusing our R&D organization on delivering the opportunities where the value is greatest to patients,” said Francis Cuss, executive vice president and chief scientific officer, Bristol-Myers Squibb. “We have decided to shift R&D toward a more specialty BioPharma model that focuses on the areas of significant unmet medical need, driving near-term growth through our current late-stage portfolio and on ensuring the long-term growth of the company by evolving the disease areas and drug platforms on which we concentrate our research efforts.”

Under this new strategic focus in R&D, Bristol-Myers Squibb will

• Continue to advance the lifecycle and late-stage pipeline, executing development, regulatory and commercial plans for the diabetes franchise, Eliquis® (apixaban),Sprycel® (dasatinib), Orencia® (abatacept), Erbitux® (cetuximab), Baraclude® (entecavir), Reyataz® (atazanavir sulfate)/Sustiva® (efavirenz), and hepatitis C.
• Increase investment in immuno-oncology, an area of significant opportunity, to realize the full potential of immunotherapy in certain cancers.
• Evolve the disease areas and drug platforms on which we concentrate our research efforts to drive growth for the company in 2020 and beyond by discontinuing broad based discovery work in hepatitis C, diabetes and neuroscience. The company will continue to focus on HIV, HBV, heart failure, oncology, immunoscience and fibrotic diseases.

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When to refer hepatitis C patients for specialist treatment

Provided by Clinical Advisor

Sally Davis, PA-C, and Claire Babcock O'Connell, MPH, PA-C

November 07, 2013

ADVISOR FORUM

I work with an incarcerated population in which 40% of my patients have hepatitis C. Given limited resources, which patients would benefit most from specialist referral? — Sally Davis, PA-C, Chico, Calif.

The standard of care for many patients with hepatitis C consists of combination therapy with an oral protease inhibitor (boceprevir [Victrelis] or telaprevir [Incivek]), along with pegylated interferon and ribavirin (Copegus, Rebetol, Ribasphere, Virazole).

Patients undergoing treatment may experience profound fatigue, depression, and a slew of side effects (e.g., blood dyscrasias, infections, muscle and joint pain, hair loss, thyroid dysfunction, psychiatric changes). The treatment is expensive and long-term (24-48 weeks, longer in the immunosuppressed).

There are four genotypes of hepatitis C. Patients with genotype 1 can expect a 40% to 45% response rate after 48 weeks of treatment. Patients with genotypes 2 or 3 can expect a 70% to 80% response rate after only 24 weeks of treatment. Studies suggest that a drop in hepatitis C viral load within 12 weeks of treatment is correlated with treatment success.

High success rates are also seen in patients with an elevated CD4 count prior to treatment and those in otherwise good health. For patients with hepatitis C who are not candidates for treatment or who have a lower chance of treatment response, it remains important to protect and support the liver as well as to keep the immune system healthy. — Claire Babcock O'Connell, MPH, PA-C (181-4)

These are letters from practitioners around the country who want to share their clinical problems and successes, observations and pearls with their colleagues. We invite you to participate. If you have a clinical pearl, submit it here.

From the November 2013 Issue of Clinical Advisor

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Supplements Blamed for Liver Toxicity

Meeting Coverage

Published: Nov 6, 2013

By Michael Smith, North American Correspondent, MedPage Today

WASHINGTON -- The rate of liver damage caused by dietary and herbal supplements -- especially those used for bodybuilding -- appears to be on the rise, a researcher said here.

Over about an eight-year period from 2004 through 2012, reported cases of hepatotoxicity caused by any type of drugs, including prescription medications, more than doubled, according to Victor Navarro, MD, of the Einstein Healthcare Network in Philadelphia.

But the proportion of cases caused by dietary and herbal supplements increased from 7% to 20% (P<0.001), Navarro reported at the annual meeting of the American Association for the Study of Liver Diseases.

The rate of injuries caused by bodybuilding supplements grew more rapidly (from 2% to 7%, P=0.01) than the rate attributed to all other forms of supplements (from 5% to 12%,P=0.05), Navarro said.

Navarro said the finding is based on 845 cases of liver damage reported to the nationwide Drug-Induced Liver Injury Network that were assessed as probably, very likely, or definitely due to the suspected agent.

Of those, 136 (or 16%) were attributed to an herbal or dietary supplement while the remaining 709 were considered to be the result of prescription or over-the-counter drugs.

The findings are not a surprise, outside experts told MedPage Today.

"It's a huge problem," commented Mary Rinella, MD, of Northwestern Memorial Hospital in Chicago, who was not part of the study but who moderated a session at which it was presented.

And it's made worse by the popular belief that such supplements are harmless, which leads patients to omit mentioning them when they are in a clinic or doctor's office, Rinella said.

She noted that there is no control over what goes into such products or the concentrations. Indeed, studies have shown that in some cases, the listed ingredient -- St. John's Wort, for instance -- may not even be in the product, she said.

"We don't know what's in the products or even what's in the bottle," Rinella said.

It's tough to figure out the true impact of such supplements, commented Donna Seger, MD, of the Tennessee Poison Center in Nashville.

But toxicologists and workers in poison control centers know "it's very prevalent," she said. "We have calls on herbals and dietary supplements all the time."

Part of the problem, she said, is that dietary and herbal supplements are not considered drugs and so escape oversight by the FDA. The products have to have a label that says what's in the product, but it's "based on the truthfulness of the manufacturer, of which there is no oversight," Seger added.

The biggest problem is liver toxicity, Seger said.

For clinicians, she said, the most important step is to ask patients if they are taking anything from health or nutrition stores. "Most people don't think this is medicine, so they don't tell their doctor that they're taking them," she said.

Navarro and colleagues tried to group the various supplements -- some 262 different products taken by the 136 patients -- into categories based on their intended use.

"It was quite difficult," he said. The only clear category turned out to be supplements intended for bodybuilding, so the investigators divided the cases into those blamed on bodybuilding products and those blamed on all other types.

After excluding seven patients who took both bodybuilding and other products, Navarro and colleagues were left with 44 cases blamed on bodybuilding products and 85 others.

Demographically, the two groups of patients were distinct, he said. Bodybuilders were younger, exclusively male, heavier, and more likely to be white.

They were also less likely to have a major co-morbidity and more likely to present with jaundice and pruritus.

Indeed, 100% of the bodybuilders had jaundice, which lasted for a median of 91 days, compared with 44 for those in the other group who had jaundice.

On the other hand, none of the bodybuilders needed a liver transplant, compared with 13% of the patients whose illness was blamed on other products, Navarro reported.

Source

All-Oral Treatment Suppresses Hep C in HIV Patients

Meeting Coverage

Published: Nov 7, 2013

Coverage of Hepatitis C Virus is supported in part by an independent educational grant from AbbVie Pharmaceuticals.

This report is part of a 12-month Clinical Context series.

By Ed Susman , Contributing Writer, MedPage Today

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

Action Points

• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• Note that this uncontrolled study of patients coinfected with HIV and HCV demonstrated that the combination of sofosbuvir and ribavirin has very good virologic efficacy.
• Be aware that all patients were on antiretroviral therapy and had undetectable HIV levels.

WASHINGTON -- An all-oral regimen to treat the hepatitis C virus (HCV) in patients co-infected with HIV appears to achieve a sustained virologic response against the hepatitis virus without disrupting suppression of the virus that causes AIDS, researchers said here.

Patients with co-infection treated with the investigative nucleotide polymerase inhibitor sofosbuvir plus the workhorse antiviral ribavirin achieved sustained virologic response at week 12 -- considered a cure for HCV infection -- in 76% of 114 patients diagnosed with HCV Genotype 1 infection said Mark Sulkowski, MD, associate professor of medicine at Johns Hopkins Medical Institutions.

Sustained virologic response was also seen in 88% of 36 patients diagnosed with HCV genotype 2 infections and in 67% of 42 patients diagnosed with HCV genotype 3 infection, Sulkowski reported at the annual meeting of the American Association for the Study of Liver Diseases.

"The interferon-free regimen of sofosbuvir plus ribavirin resulted in high sustained virologic response at week 12 rates in hepatitis c virus treatment naïve, HIV-infected patients that were similar to those seen in patients with hepatitis c virus mono-infection," he said in his plenary sessions presentation.

Almost all patients responded to treatment -- 100% of those with genotype 1, 96% of those with genotype 2, and 98% of those with genotype 3.

The regimen was well tolerated by patients who had a variety of antiretroviral therapies. "HIV viral breakthrough was seen exclusively in the setting of poor antiretroviral compliance," Sulkowski said. Furthermore, treatment with the all-oral hepatitis C therapy did not appear to affect levels of CD4-positive cell counts in the patient cohort.

"This is a dramatic new development," Raymond Chung, MD, professor of medicine at Massachusetts General Hospital/Harvard Medical School, told MedPage Today. "It is something that the FDA will take into serious consideration in its labeling." He said that being an all-oral combination gives it advantages over other treatments.

In the study, Sulkowski and colleagues, recruited patients co-infected with the two viral diseases. The mean age of the patients was about 48, about 80% were men and about 33% of the genotype 1 patients were black.

The 114 patients diagnosed with genotype 1 were treated with sofosbuvir and ribavirin for 24 weeks and then they were followed for 12 more weeks to determine if there was a sustained virologic response. The 68 patients diagnosed with genotype 2 and genotype 3 were treated with 12 weeks of therapy, followed again for 12 weeks to determine if sustained virologic responses had been achieved.

"We used broad inclusion criteria," Sulkowski said. Patients with cirrhosis were allowed to enroll; and a wide range of HIV regimens were also permitted as long as the patients had undetectable viral loads and were on a stable antiretroviral regimen. If patients had CD4-positive cell counts greater than 500 cells/mm³ they were also eligible for the trial.

Sulkowski said, in response to questions from the audience, that no control group was used in the study because of medical and ethical concerns.

Sulkowski disclosed commercial relationships with Pfizer, Merck, AbbVie, BIPI, Vertex, Janssen, Gilead, and Bristol-Myers Squibb

Chung disclosed commercial relationships with Idenix, Enanta, Gilead, Merck, and Mass Biologic.

Primary source: American Association for the Study of Liver Diseases.
Source reference: Sulkowski M, et al "All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1)"AASLD 2013.

Source

Also See: Gilead Announces Phase 3 Results for an All-Oral, Sofosbuvir-Based Regimen for the Treatment of Hepatitis C in Patients Co-Infected With HIV

Research tackles liver transplant failure

Provided by MedicalXpress

November 7, 2013

The re-infection of transplanted livers with hepatitis C virus (HCV) – which can irreparably damage the new organ - could be halted by administering a drug which blocks the virus entering the liver, research from the University of Birmingham being presented at the Liver Meeting demonstrates.

People who receive a new liver to replace their own organ previously damaged by HCV infection are 95 per cent likely to experience recurrent infection after the transplant, where virus levels can surpass the pre-transplant levels within a few days. Importantly, viral replication and ensuing injury can be more aggressive after the transplantation.

This often means that the new liver becomes damaged, and to a level at which it can cease to function in just a few years. As many as a quarter of HCV infected patients who receive a transplant will experience liver failure, possibly leading to death, within ten years.

Until now, doctors have been unable to prevent HCV, which circulates in the bloodstream, from entering the new liver – however results from a trial at Birmingham evaluating a HCV entry inhibitor drug, ITX5061, given before, during and after the transplant dramatically slows down the progress of the virus re-infecting the liver. Although the drug did not clear HCV completely from the blood of the patients, the results of this research suggest that it could be used as a treatment in conjunction with more conventional strategies.

The trial involved 23 patients undergoing liver transplantation. Thirteen control patients did not receive the drug, and the remaining 10 patients were given ITX5061 on the day of their transplant and for a week afterwards. The levels of HCV in all participants' blood were measured at set time points, with a greater decline noted for all patients treated with ITX5061.

The trial was carried out by researchers at the Centre for Liver Research and NIHR Birmingham Liver Biomedical Research Unit at the University of Birmingham, in conjunction with colleagues at the Queen Elizabeth Hospital Birmingham.

Dr Ian Rowe, who presented the research, said: "This is the first trial in patients undergoing liver transplantation of a drug that blocks HCV entry into the new liver. Until now we have only been able to study this process in the laboratory and this study has allowed us to learn about this process as it happens in patients. ITX5061 treatment was safe and we hope that further studies of this drug in combination with others in development will improve the outcomes for this challenging group of patients."

The findings, Scavenger receptor B-I antagonist ITX5061 modulates early HCV kinetics in patients undergoing liver transplantation: results of a phase Ib clinical trial, were presented on Sunday (November 3) at the Liver Meeting, the Annual Meeting of the American Association for the Study of Liver Disease in Washington DC.

HCV is the second biggest cause of chronic liver disease leading to a transplant in the UK, and the leading cause in the USA. The Health Protection Agency (HPA) estimate that by 2020 15,840 individuals will be living with hepatitis C-related cirrhosis or cancer in England, more than 4,200 with decompensated cirrhosis or cancer for whom a liver transplant may be the only option.

Explore further: Aging hepatitis C population escalates demand for liver transplantation

Provided by University of Birmingham

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Hepatitis C, stigma and cure

World J Gastroenterol. 2013 October 28; 19(40): 6703-6709.

Published online 2013 October 28. doi: 10.3748/wjg.v19.i40.6703.

Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.

Rui Tato Marinho and David Pires Barreira.

Rui Tato Marinho, David Pires Barreira, Department of Gastroenterology and Hepatology Hospital Santa Maria, Medical School of Lisbon, 1649-035 Lisboa, Portugal

Author contributions: Both of authors gave substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, and final approval of the version to be published.

Correspondence to: Rui Tato Marinho, MD, PhD, Department of Gastroenterology and Hepatology, Hospital Santa Maria, Medical School of Lisbon, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal. rui.marinho@mail.telepac.pt

Fax: +351-217-805678

Received July 28, 2013; Revised August 14, 2013; Accepted August 17, 2013;

Abstract

The infection with hepatitis C virus (HCV) is one of the most important global chronic viral infections worldwide. It is estimated to affect around 3% of the world population, about 170-200 million people. Great part of the infections are asymptomatic, the patient can be a chronic carrier for decades without knowing it. The most severe consequences of the chronic infection are liver cirrhosis and hepatocellular carcinoma, which appears in 20%-40% of the patients, leading to hepatic failure and death. The HCV was discovered 25 years ago in 1989, is a RNA virus and classified by the World Health Organization as an oncogenic one. Hepatocellular carcinoma is one of the most important cancers, the fifth worldwide in terms of mortality. It has been increasing in the Ocidental world, mainly due to chronic hepatitis C. Hepatitis C is not only a liver disease and a cause of cirrhosis, but also a mental, psychological, familiar, and social disease. The stigma that the infected person sometimes carries is tremendous having multiple consequences. The main cause is lack of adequate information, even in the health professionals setting. But, besides the “drama” of being infected, health professionals, family, society and the infected patients, must be aware of the chance of real cure and total and definitive elimination of the virus. The treatment for hepatitis C has begun in the last 80´s with a percentage of cure of 6%. Step by step the efficacy of the therapy for hepatitis C is rapidly increasing and nowadays with the very new medications, the so called Direct Antiviral Agents-DAAs of new generation, is around 80%-90%.

Keywords: Hepatitis C, Chronic, Therapy, Hepatocellular carcinoma, Hepatic cirrhosis, Interferon-alpha, Ribavirin, Social stigma, Depression

Core tip: Around 3% of the world population, about 170-200 million people are infected with hepatitis C virus. The chronic consequences of the infection are liver cirrhosis and hepatocellular carcinoma, which appears in 20%-40% of the patients. Hepatitis C is not only a liver disease but also a mental, psychological, familiar, and social disease. The stigma that the infected person sometimes carries is tremendous. But, besides the “drama” of being infected, health professionals, family, society and infected patients, must be aware of the chance of real cure and definitive elimination of the virus. Step by step, the efficacy of the therapy for hepatitis C is rapidly increasing and with the new medications, the Direct Antiviral Agents-DAAs, is around 80%-90%.

HEPATITIS C AND CURE

Step by step increasing the efficacy

Hepatitis C is one of the most important global chronic infection worldwide: it is estimated to affect 170-200 million people, while chronic hepatitis B and human immunodeficiency virus (HIV) infection affects respectively 350 million and 34 million. There is no vaccine for hepatitis C. Hepatitis B is easily preventable by vaccination. Another characteristic of hepatitis C virus (HCV) infection is the high risk of evolution to chronicity, more than 50% which can be around 80% in same series[¹]. Another characteristic is the absence of symptoms for decades before the phase of decompensation of liver cirrhosis and the appearance of hepatocellular carcinoma.

The most severe chronic consequences of the infection are liver cirrhosis and hepatocellular carcinoma, leading to hepatic failure and death, which can appear in 20%-40% of the patients[²].

In effect, cirrhosis is the end-stage of every chronic liver disease. Its natural history is characterized by an asymptomatic phase, called “compensated” followed after several years or decades by a “decompensated” phase. The patient, in the decompensated phase has a median of survival of 2 years[³].

This phase can be characterized by a rapid clinical evolution with all the complications of a cirrhotic liver with portal hypertension: ascites, sepsis (the majority from spontaneous bacterial peritonitis), varices bleeding, jaundice, mental alterations (encephalopathy), renal failure (hepatorenal syndrome), caquexia[^4,5].

Liver cirrhosis is one of the most oncogenic situations in medical terms. The development of hepatocellular carcinoma (HCC) is a real fact, occurring in 1%-4% each year and is becoming in some centers the most frequent complication of HCV cirrhosis[⁶].

The quality of life in the decompensated phase can be very poor with frequent hospitalizations and readmissions[⁷]. At this stage only liver transplantation is really effective for median or long term survival. But if the virus is still active, the reinfection is almost universal[⁸]. But, besides the “drama” of being infected, health professionals, family, society and infected patients, must be aware of the chance of real cure and total and definitive elimination of the virus[⁹].

The HCV was discovered 25 years ago in 1989, is a RNA virus and classified by the World Health Organization as an oncogenic one[¹⁰]. The discover of the virus has open the way to a diagnosis test (anti-HCV) and several studies of molecular biology, virology and pharmacology[¹¹]. The treatments for hepatitis C has begun in the last 80´s with a percentage of cure of 6%[¹²]. Step by step the efficacy of the therapy for hepatitis C is rapidly increasing and nowadays with the very new medications, the oral Direct Antiviral Agents-DAAs, is around 80%-90%[¹³].

The therapy of hepatitis C is an example of the capacity of modern medicine to translate the basic research to the clinical setting (Figure 1). Several types of medications have been used in to treat hepatitis C throughout these 25 years of success: first, human interferon (INF, three times weekly, 6% of efficacy), in 1995 Ribavirin has appeared to be used in combination with INF (34%-42% of efficacy), in 2001 Pegylated INF once weekly with ribavirin (45% of cure for genotype 1 and 70%-80% for genotype 3)[¹⁴]. In 2011 another step with the combination of Peginterferon and Ribavirin with two Protease inhibitors, region 3/4 (Boceprevir[¹⁵] and Telaprevir[¹⁶]), the triple therapy, leading to cure in 70%-80% of cases.

Figure 1 Percentage of cure of hepatitis C genotype 1. IFN: Interferon; RBV: Ribavirine; PEG: Peginterferon; DAA: Direct antiviral agents.

Several clinical trials are in rapid development worldwide with the new DAA´s (Direct Acting Antiviral Agents) interacting with several of vital components of the virus (NS 3/4, NS5A, NS5B Polymerase, etc.). In effect a new generation medications is rapidly approaching, like Sofosbuvir[¹³], Daclastavir, Asunaprevir[¹⁷], ABT-450[¹⁸], Faldaprevir, Simeprevir, Deleobuvir, some of them only using oral agents, for a period of 12 wk, with a few negligible side effects, having a chance of viral eradication of 80%-90%.

In fact, in a quarter of a century, the percentage of cure has increased from 6% to 90% of cure. From three injections a week during 48 wk to some pills a day during 12 wk! Another important development that has positively affected the quality of life of patients, allowing access to treatment and possible cure is the Transitory Elastography (Fibroscan^®). Is an ultrasonographic device with very good acuity in the diagnosis of liver fibrosis, mainly when there is liver cirrhosis. The number of liver biopsies has decreased[¹⁹] in some centers around 90%.

The efficacy of the therapy is assessed by on important finding, i.e., the viral load: RNA HCV (by a sensitive test) must be negative 24 wk after stopping therapy. If this happens, more than 99% of patients will never be positive again.

Cure of hepatitis C

It is the only global chronic viral infection that is possible to cure. The other ones are hepatitis B and HIV infecting respectively 350 and 34 million people worldwide but with no chance of cure in chronic cases.

In the beginning of this story of success, the medical community was afraid of the word cure. But now it is well known this word can be used with property but with some restrictions. In effect is a virological cure for life. It is proved that virus is not detected on liver cells or mononuclear blood cells. Nor there is an occult disease as is the case for chronic hepatitis B (HBV DNA negative or with low levels, having HBsAg negative and a risk of relapse in case of immunosuppression).

Albeit is a definitive one, we must be cautious in patients having liver cirrhosis, because the chance of development of hepatocellular carcinoma is strongly reduced, but still remains. It is one of the reasons to treat patients with mild or moderate fibrosis, in order to reduce the chance, while in a stage of a less severe disease, of evolution to cirrhosis and hepatocellular carcinoma. Liver cirrhosis, per se, is a disease having a risk of 1%-4% per year of evolution to hepatocellular carcinoma.

The benefits of cure are tremendous. Hepatitis C should be considered a global disease. As for the definition of Health of World Health Organization, (“Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity”) chronic hepatitis C is a physical, mental and social disease, affecting globally the individual, the couple, the family, and the society as a whole.

There are some myths about hepatitis C: “almost always lethal, more severe than acquired immunodeficiency syndrome (AIDS), very contagious disease, not curable, the adverse events of therapy are huge and very severe, etc.” But the benefits of cure, in global terms considering the physical, mental and social aspects are several (Table 1).

Table 1 Benefits of cure of hepatitis

• Negative HCV RNA (viral load) for life, in more than 99% of cases
• Negative HCV RNA in the liver
• HCV RNA negativation in PBMC
• No detection of the genotype
• Sometimes, a few year later, the anti-HCV test can became negative, the so called “seroreversion”
• Normalization of aminotransferases (AST, ALT) and GGT
• Changing of ultrasound findings (contours can became regular, reduce of diameter of portal vein in case of portal hypertension)
• Disappearance of the lymphnodes near the liver (helium)
• Decrease of the values for Elastography (Fibroscan^®)
• Reducing the risk of progression to cirrhosis
• Reversion of cirrhosis in some cases
• Disappearance of oesophageal varices
• Reducing the risk of progression to liver cancer
• Reduced risk of decompensated liver disease (ascites, jaundice, rupture of oesophageal varices, encephalopathy)
• Reducing to zero the risk of recurrence after liver transplantation (if necessary)
• Improved quality of life (asthenia, fatigue, general well-being)
• Reducing of the psychological impact (anxiety/depression)
• Disappearance of the risk of sexual transmission
• Disappearance of the risk of perinatal transmission
• Decrease in the insurance premium
• Cure of associated conditions (porphyria cutanea tarda, polyneuropathy, urticaria, cryoglobulinemia, splenic lymphoma)
• Reducing personal, family and social stigma
• The treatment is proved cost-effective
• Benefit to public health
• Reduced risk of death from liver disease
• Neurocognitive improvement
• Cure of hepatitis C

Benefits of virological response (HCV RNA negative 24 wk after finishing therapy). HCV: Hepatitis C virus; PBMC: Peripheral Blood Mononuclear Cells; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: Gamma-glutamyl transferase.

Mental health and quality of life in hepatitis C

Besides the natural history of this disease, the personal impacts of a diagnosis of hepatitis C infection and its treatment strongly affect the patients’ quality of life[^20-22]. Mental health problems frequently occur in chronic infection with HCV and during the antiviral treatment. These individuals frequently present neuropsychiatric symptoms like fatigue, anxiety, depression and cognitive disorders[^23,24].

Regarding neuropsychiatric symptoms, one can identify two distinctive patterns in its relation with HCV infection. On one hand, individuals with chronic hepatitis C have higher prevalence of psychiatric disorders, including depression[²⁵]. On the other hand, individuals with psychiatric records present higher HCV infection rates than the average population[²⁶].

A combined therapeutics using Pegylated IFN is commonly used in these patients and proves to be a fundamental and consensual intervention for a favourable change in the natural history of the disease[^27,28].

However, this treatment is associated with a high number of adverse reactions like: irritability, insomnia, fatigue and loss of appetite. Apart from these, neuropsychiatric symptoms (especially depression, and sometimes with suicidal ideation) are among the most common secondary effects in therapeutics with IFN, being one of the main causes why patients interrupt their treatment[^24,29,30]. It is noteworthy that, up to a certain extent, psychopathologic symptoms (depression, cognitive disorders) may be associated to HCV infection, even without an INF treatment, and may be related to direct HCV neurotoxicity[^29-32].

A large number of patients undergoing treatment for VHC infection should be referred for psychiatric evaluation and, if necessary, should received treatment for depression and other neuropsychiatric symptoms.

Recognition of depression and other neuropsychiatric symptoms is important, and could improve adherence to VHC treatment. This symptomatology negatively affects the individual’s perceived quality of life, its general functioning, work capacities, less participation in life and medical care, increase mobility and mortality, decrease overall well-being and quality of life[^27,33]. Furthermore, therapeutic used in HCV treatment is associated to impairment in all of these dimensions[³⁴].

Thus, considering the impact in patients’ mental health, before and during the treatment, an interdisciplinary approach should be followed and encouraged when dealing with HCV infected patients[²⁴].

Stigma and hepatitis C

Diagnosis with hepatitis C was reported to have profound impacts on social functioning. Perceived stigma associated with HCV infection leads to high levels of anxiety and exaggerated fear of transmission, and it can be a major cause of social isolation and reduced intimacy in relationships[³⁵].

Epidemiological studies suggest that more than 90% of transmission in developed countries takes place through the sharing of non-sterilized needles and syringes in the intravenous drug-using population[³⁶].

Because the vast majority of people with hepatitis C have a history of intravenous drug use, they are frequently blamed for acquiring the disease, and viewed as irresponsible, accountable and “unworthy”[³⁷]. Furthermore, as a blood-borne disease, hepatitis C is strongly associated with HIV. This association exists due to the fact that intravenous drug abuse is a significant risk factor for contracting both diseases and this can be a stigmatizing factor for this patients[³⁸]

Stigma can be defined as attitudes expressed by a dominant group, which views a collection of others as socially unacceptable. The notion of stigma denoting shameful relations and deviations from what is considered “normal” has a long history within infections disease, in particular HIV[³⁹], and more recently in hepatitis C infection.

These norms, behaviours and beliefs surrounding hepatitis C infection can lead to alienation from family and friends, as well as to discrimination (perceived or real) in health services and workplaces[⁴⁰].

Stigma can affect self-esteem and quality of life. It can also impede the success of diagnosis and treatment, leading to continuing risk of disease transmission. It is a social phenomenon that influences the course of illness and marginalizes patients[⁴¹].

Since stigmatization affects not only the individual but also the whole course of the disease, health care workers are not immune to stereotypes and judgements that might influence the course of the treatment of HCV patients. Changing this behaviour will help prevent patients’ isolation, withdrawal of treatment and it will increase the search for medical help[⁴²].

Hepatitis C should have a global approach in its treatment. It requires broad-based educational efforts in order to increase the understanding of this disease, still connected to several pejorative stereotypes[⁴²]. These efforts should include patients and their family, health care providers and the society as a whole. Further knowledge of hepatitis C stigma is central to assisting patients in self-managing their illness, and it is important to reduce the disease burden.

Several benefits of cure hepatitis C

The goal of therapy is to eradicate HCV infection. The endpoint of therapy is sustained virological response (SVR). Once obtained, SVR usually equates to cure of infection in more than 99% of patients[⁴³].

If the test for assessing viral load is negative 24 wk after finishing therapy, we can talk of “cure”. With the new treatments, the oral DAAs, the assessment of sustained viral response can be shortened to 12 wk after ending the treatment. HCV RNA detection and quantification should be made by a sensitive assay (lower limit of detection of 50 IU/mL or less), ideally a real-time PCR assay. If the patient has already cirrhosis, the risk of develop hepatocellular carcinoma still persist for some years and deserves an abdominal ultrasound every six mouths.

When the SVR is obtained the global benefit is as it follows: if there is no another reason for AST, ALT or GGT elevation, namely alcohol consumption or obesity, they became persistently normal.

At virological level, the HCV RNA is no longer detected in the liver[⁴⁴] or even in the Peripheral Blood Mononuclear Cells (PBMC) by sensitive tests[⁴⁵]. The genotype becomes and remains negative, because there is no virus for detection.

One of the things that can cause some confusion is the fact that the anti-HCV (a marker of past infection) generally remains positive. The index can decrease slowly and the anti-HCV can became negative, several years after, as it happens in the context of acute hepatitis C[⁴⁶].

On the Hepatic Elastography (Fibroscan^®) the values generally decrease along some months[⁴⁷]. At the abdominal ultrasound the findings can change: the liver contours can become regular, the diameter of portal vein reduces in case of presence of portal hypertension. The disappearance of the lymph nodes in the hepatic hilum can be a finding[⁴⁸]. There are some studies showing thatdimensions of these lymph nodes are related with the levels of viral replication[⁴⁹].

Regarding liver disease the risk of progression to cirrhosis decreases. In some cases it occurs a reversion of cirrhosis[⁵⁰]. In fact this is no longer an irreversible situation as was thought some years ago; the disappearance of oesophageal varices is also fact[⁵¹]. On the other side, there is a decrease of risk of evolution for more severe stages of liver disease like the progression hepatocellular carcinoma[⁵²] and risk of the decompensated liver disease (ascites, jaundice, rupture of oesophageal varices, encephalopathy, jaundice, etc.)[⁵³].

In the case that a liver transplantation would be necessary the risk of reactivation is no longer present. More than 95% of cases of patients transplanted for cirrhosis associated with HCV will have again HCV RNA positive and 50% will develop severe forms of liver disease a few years after transplant[⁵⁴]. Because of that, to treat patients with cirrhosis or intense fibrosis must be done as soon as possible.

There is an improvement of quality of life[⁵⁵] (asthenia, fatigue, general well-being, etc.) assessed by adequate tests and more important on the mental level there is a reduction of the psychological impact (anxiety and/or depression).

In strong relation to cure, the risk of sexual[⁵⁶] and perinatal transmission[⁵⁷] disappear. These are very important advantages of SVR in the treatment of hepatitis C. We must not forget, that hepatitis C, besides a liver disease is also an infectious and transmissible disease. We can consider the cure as “belonging” to the patient himself but also to his family, his couple, etc. Is also a familiar disease. There are some patients who don´t tell the family or to the couple afraid of the consequences of the bad new. If patients insist with Insurance Companies they must decrease the insurance premium because there is less risk of clinical evolution.

There are reports of the control and even disappearance of some associated conditions like porphyria cutanea tarda[⁵⁸], polyneuropathy[⁵⁹], urticaria[⁶⁰], cryoglobulinemia[⁶¹], splenic lymphoma[^62,63].

Depending on the countries and the burden of the infection, the treatment was proved to be cost-effective[⁶⁴]. Reducingof personal, psychological, family and social stigma is a huge benefit for all. Stigma is a fact that must be considered in the setting of HCV therapy and also when considering the real burden of the disease.

CONCLUSION

Considering the global approach we can consider that to cure HCV chronic infection is a real benefit to public health mainly by reducing the risk of complications and dying because of liver disease. Having access to the most modern therapies, the disease is almost a curable disease and the efficacy of treatment markedly increases the survival of patients infected. Chronic hepatitis C is a silent epidemic, a global disease with a strong stigma, but with high chance of definitive cure[⁶⁵].

Footnotes

P- Reviewers Boin I, Tang W S- Editor Song XX L- Editor A E- Editor Zhang DN

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