Even With ACA, Many May Be 'Underinsured'

Published: Jan 2, 2014

By Michelle Andrews , Kaiser Health News

People with chronic conditions will be better protected from crippling medical bills starting in January as the health law's coverage requirements and spending limits take effect. But a recent analysis by Avalere Health found that many may still find themselves "underinsured," spending more than 10% of their income on medical care, not including premiums, even if they qualify for cost-sharing subsidies on the health insurance marketplaces.

"You have some great protections in place, but these out-of-pocket costs and how plans are structured are going to create some serious problems," says Marc Boutin, executive vice president at the National Health Council, an advocacy group for people with chronic health conditions.

Potential trouble spots include prescription drugs; specialist care, including that provided by academic medical centers; and services such as physical therapy that typically require a course of treatment over weeks or months, say experts.

The health law prohibits insurers from turning down sick people for coverage and generally eliminates lifetime and annual dollar limits on benefits, including hospitalization and prescription drugs.

It also caps the amount people spend out-of-pocket in 2014 at $6,350 for individuals and $12,700 for families that buy a plan on the individual and small group markets, including the health insurance exchanges. People with incomes below 250% of the federal poverty level ($28,725 for an individual or $58,875 for a family of four in 2013) may qualify for cost-sharing subsidies on the marketplaces that reduce those caps as well as their deductibles and copayments.

The Avalere analysis found that many chronically ill people, especially those in Bronze or Silver plans that offer less generous coverage, will likely reach their out-of-pocket maximum every year.

John Earley worries he may be one of them. Earley, 60, has severe plaque psoriasis.

After he was diagnosed more than 30 years ago, topical creams and ultraviolet light treatments that slow the growth of skin cells worked for a while. But eventually their effectiveness waned. He finally found relief with Humira, a biologic drug that blocks the production of an immune system protein that causes inflammation. The twice monthly injections cost more than $2,200, but the Texas high-risk pool through which Earley and his wife are insured covers the drug with a $100 copayment. The drug's manufacturer, AbbVie, covers all but $5 of that amount through its patient assistance program. Their insurance premium is $1,460 per month.

With the Texas high-risk pool set to close early next year, Earley, who works on contract as an architect in Arlington, is checking into plans on the health insurance marketplace. The plan with the best Humira coverage -- a $150 copay per refill -- is a gold plan with a $1,718 monthly premium for the two of them, says Earley. Plans with lower premiums would require 40% to 50% coinsurance for the drug, which is in a high-cost specialty tier.

"What I'm finding with the insurance policies that are available, it's going to cost you either way," says Earley.

The gold plan with the best Humira coverage would cost roughly a quarter of their income, says Earley, who is not eligible for tax credits to subsidize his premium costs. But that may be their best option, even with financial assistance from the drug's manufacturer, given the high drug coinsurance charges on the other plans.

Drug costs are perhaps the most often cited coverage concern for people with chronic conditions, but there are others, say experts.

Access to specialists and to academic medical centers with the necessary expertise can be problematic on the marketplaces, where many insurers have opted for a narrow network of doctors and hospitals in order to keep a lid on premiums. A recent McKinsey & Co. study found that 70% of the 120 plans it examined offered narrow hospital networks that excluded at least 30% of an area's biggest hospitals. Academic medical centers were generally part of broader plans whose premiums were 10% higher than average.

For people who need specialist care, narrow networks can be problematic since the law's limits on what a patient spends out-of-pocket only apply to in-network care. Dermatologists trained in handling severe psoriasis may not be in network, nor the academic medical centers that some people need for treatment, says Leah Howard, director of government relations and advocacy at the National Psoriasis Foundation.

On the other end of the spectrum, sometimes the out-of-pocket costs for effective treatments such as phototherapy can deter patients who would have to make a copayment for perhaps dozens of sessions.

"We've seen people who would prefer to be on phototherapy, but can't afford $500 in copays over eight weeks, so they end up stepping up to a systemic treatment," says Howard.

In addition, although dollar limits on benefits aren't allowed, plans typically limit the number of sessions for certain treatments such as physical therapy.

Because of the rocky rollout of the exchange websites in many states, many consumers have found it difficult to get basic information about premiums and plan deductibles, say experts. Many don't know which providers are in the plan networks or what benefits the plans cover.

"As more and more people become covered and as people start to use their plans, we'll see if the cost protections in the plans are sufficient, and directed toward getting people the care they need," says Sara Collins, a vice president at the Commonwealth Fund.

This article, which first appeared Dec. 31, 2013, was reprinted from kaiserhealthnews.orgwith permission from the Henry J. Kaiser Family Foundation. Kaiser Health News, an editorially independent news service, is a program of the Kaiser Family Foundation, a nonprofit, nonpartisan health policy research and communication organization not affiliated with Kaiser Permanente.

Source

Gilead Seeks To Expand Its Blockbuster Hepatitis Platforms In 2014

Provided by Seeking Alpha

Jan. 3, 2014 2:27 AM ET |  About: GILD, Includes: MRK, VRTX

Henry Kawabe

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.

Gilead Sciences (GILD) received approval earlier this month for what may well be one of the most successful drugs to be approved in years -- Sovaldi, its novel hepatitis drug. Sovaldi, which some analysts say can actually cure some hepatitis cases, is expected to be a blockbuster for the company and could see sales surpassing $8 billion annually by 2018. On the heels of the approval, Gilead announced that it will now seek U.S.approval for a combination of Sovaldi and its newest hepatitis drug -- ledipasvir -- in the first quarter of 2014. The combination of these two drugs could be a "one-two knockout"… not just of the disease, but of the competition as well.

The National Institute of Health estimates that 180 million people have the hepatitis virus. What is interesting is that less than 50% of those people have been diagnosed, and less than 10% have been treated. Chronic hepatitis C affects roughly 4 million people in the U.S., and the costs for treating the disease is roughly $40 billion annually, and is expected to more than double over the next 20 years to $85 billion. Hepatitis is the leading cause of liver cancer, which has passed HIV/AIDS in the number of deaths. The current hepatitis drug market is estimated to be at $5 billion annually and expected to triple by 2018. That leaves a very big market opportunity, especially for companies developing far less invasive treatments. This is why a number of drug companies, including Abbyville, Johnson & Johnson, and Vertex Pharmaceuticals, have been competing with Gilead in racing to be the front-runner in battling hepatitis.

Hepatitis Treatments Have Advanced Greatly Over The Past Three Years

Up until a short time ago, the treatment for hepatitis had comprised of weekly injections of interferon alfa for 24 to 48 weeks, along with daily tablets of the anti-viral, ribavirin. The treatment cure rate was about 50%, and the side effects were brutal. In 2011, two new drugs -- Incivek from Vertex (VRTX) and Victrelis from Merck (MRK) -- gained FDA approval in combination with the existing treatment. These highly touted drugs shortened the treatment time in some cases to 24 weeks, and increased the cure rate for genotype 1 from 60% - 80%. And while at one time these promising drugs looked to be future blockbusters, they will probably see minimal sales as the new hepatitis drugs hit the market. Case in point is Incivek, which has already experienced a drop of 51% in sales in the fourth quarter 2012, as patients wait for the new drugs to hit the market. At one time, Incivek had sales forecasted to reach $4 billion; now these forecasts have been lowered to $669 million by 2016, roughly an 84% drop.

Sovaldi Is Designed To Stop The Hepatitis Virus From Replicating

The reason for the drop in Incivek sales is Sovaldi -- a once-daily oral nucleotide analog polymerase. And unlike previous medications to treat hepatitis, Sovaldi will not require injections of interferon (responsible for the brutal side effects) in some cases. Basically Sovaldi inhibits the virus's polymerase enzyme -- and the polymerase enzyme is what builds new genomes out of RNA allowing the virus to replicate. The drug has demonstrated its ability to cure up to 90% of patients treated after 12 weeks.

Gilead acquired Sovaldi in 2011 when it purchased Pharmasset for $11 billion. And while the purchase represented an 89% premium over Pharmasset's stock price prior to the announcement, Gilead should more than make up for the high premium now that the drug has FDA approval, making what at first appeared to be an overpriced purchase into a wise strategic investment. Sovaldi is currently approved for genotypes 1-4, and is the first oral treatment regimen for genotypes 2 and 3, and for patients waiting for a liver transplant. Sovaldi clearly makes Gilead the front-runner in the hepatitis drug market; and if it gains approval of its new drug combination, it should further its lead against its competitors.

The FDA still recommends taking interferon with Sovaldi and the oral anti-viral drug -- ribavirin -- for 12 weeks for patients with disease genotypes 1 and 4 (type 1 is the most common). But patients ineligible for interferon or who have liver cancer can just take Sovaldi and ribavirin. That combo is recommended for 12 weeks for patients with genotypes 2 and 3. That is where the combination with ledipasvir, a promising new class of drug that works by blocking the NS5A protein (which the virus also needs to replicate) comes in.

Gilead's Drug Combination May Cure Hepatitis Without Interferon

Gilead made its decision to seek FDA approval based on three late stage clinical trials where the combination of drugs, taken orally once daily in a fixed dose combination, produced a high cure rate in as short as 8 weeks with patients with genotype 1, the most common strain of hepatitis C, but also the most difficult to treat. In a 12-week regimen of the Sovaldi and ledipasvir along with anti-viral drugs ribavirin or GS-9669, the combination cured 100% of the study patients who had genotype 1 and advanced liver fibrosis or cirrhosis. And that was without the need of interferon injections.

Some analysts predict sales of Sovaldi could hit $2 billion in 2014; and once the drug combination is approved, Sovaldi could possibly work its way to become one of the world's top selling drugs. Sanford Bernstein analyst, Geoffrey Porges, commented on the upside of the new drug combination, pointing out that the tough-to-tolerate older drugs have led to thousands of patients delaying treatment for hepatitis, which could be potentially fatal. "The results certainly raise the bar and dim the outlook for competitors such as AbbVie, Bristol-Myers and Boehringer Ingelheim."

Mr. Porges pointed out that even though Gilead's competitors have all-oral programs in development, these programs will require more drugs and more pills than Gilead's to achieve similarly high cure rates. Additionally, the data coming out on Gilead's new drug combination could spell the end of ribavirin use and greatly expand the number of people seeking treatment. Therefore, Mr. Porges raised his peak sales forecast for Gilead's combination to $16 billion in 2016; however, he does see sales declining to $6.8 billion by 2020 as the backlog of patients awaiting treatment declines.

Stifel analyst, Joel Sendek, too sees the hepatitis drug combination as a blockbuster, but is a little less optimistic, forecasting sales in 2015 of $5.1 billion. There is a caveat -- and that is the extremely high cost. Gilead has priced each pill at about $1000, meaning a 12-week treatment can run $84,000, which makes the treatment unaffordable for many patients. This may be why competitors like AbbVie have the best chance of competing with Gilead, as many feel that its drug combination (currently in phase III tests) would likely be offered at a discount. Thus, it may put pressure on Gilead to adjust its pricing structure.

Gilead Science is a $115 billion company. The company stock has had an excellent run YTD, up over 100%. As a testament to its drive to refill its pipeline, Gilead has made 10 strategic purchases of companies since 2006, including Pharmasset. Through these purchases and with its own in-house developments, the company currently has 3 drugs in regulatory submission, 6 drugs in phase III trials, and 14 in phase II trials.

Better-than-expected sales helped Gilead beat 3rd quarter revenue estimates. Revenue rose 15% to $2.78 billion, beating Zacks estimate of $2.74 billion. And the company earned $0.50 per share, beating Zacks estimate of $0.47 per share. On Dec 20th JPMorgan Chase upped its target price on shares of Gilead to $100.00 per share, giving the stock a 25% upward potential. Separately, on December 20th, RBC Capital raised its target price from $80.00 to $90.00 on the stock. Gilead's stock closed on Friday December 26th at $74.45 per share.

Conclusion

Sovaldi has a number of factors that are working in its favor including a high cure rate, a reduction in treatment time, plus the elimination of the need for interferon injections in many cases. That alone should continue to send the stock to new highs. However, when one then adds in the combination of ledipasvir, if approved by the FDA sales will surely be bolstered. I believe that Gilead's stock, even though it has risen greatly this year, has the potential to reach and exceed $100.00 per share in the coming year.

Source

Preclinical Characterization of GSK2336805, a Novel Inhibitor of Hepatitis C Virus Replication That Selects for Resistance in NS5A

Antimicrob Agents Chemother. 2014 Jan;58(1):38-47. doi: 10.1128/AAC.01363-13. Epub 2013 Oct 14.

Walker J, Crosby R, Wang A, Woldu E, Vamathevan J, Voitenleitner C, You S, Remlinger K, Duan M, Kazmierski W, Hamatake R.

Abstract

GSK2336805 is an inhibitor of hepatitis C virus (HCV) with picomolar activity on the standard genotype 1a, 1b, and 2a subgenomic replicons and exhibits a modest serum shift. GSK2336805 was not active on 22 RNA and DNA viruses that were profiled. We have identified changes in the N-terminal region of NS5A that cause a decrease in the activity of GSK2336805. These mutations in the genotype 1b replicon showed modest shifts in compound activity (<13-fold), while mutations identified in the genotype 1a replicon had a more dramatic impact on potency. GSK2336805 retained activity on chimeric replicons containing NS5A patient sequences from genotype 1 and patient and consensus sequences for genotypes 4 and 5 and part of genotype 6. Combination and cross-resistance studies demonstrated that GSK2336805 could be used as a component of a multidrug HCV regimen either with the current standard of care or in combination with compounds with different mechanisms of action that are still progressing through clinical development.

PMID: 24126581 [PubMed - in process]

Source

Liver function breath tests for differentiation of steatohepatitis from simple Fatty liver in patients with nonalcoholic Fatty liver disease

J Clin Gastroenterol. 2014 Jan;48(1):59-65. doi: 10.1097/MCG.0000000000000036.

Tribonias G, Margariti E, Tiniakos D, Pectasides D, Papatheodoridis GV.

Abstract

GOALS: We investigated the utility of liver function breath tests [C-Aminopyrine Breath Test (C-ABT), C-Galactose Breath Test (C-GBT)], for the diagnosis of nonalcoholic steatohepatitis (NASH) among nonalcoholic fatty liver disease (NAFLD) patients.

BACKGROUND: Liver biopsy is currently the gold standard for the differentiation between simple fatty liver (NAFL) and NASH in NAFLD patients.

MATERIALS AND METHODS: Thirty-six patients with histologically proven NAFLD (NAFL:16, NASH:20) underwent C-ABT and C-GBT. The results were expressed as the percentage of administered C dose recovered per hour (%dose/h) and as cumulative percentage of administered C dose recovered over time (%cumulative dose). Histologic lesions were scored according to Brunt and Kleiner's classifications.

RESULTS: C-ABT results correlated inversely with activity grade (r=-0.650, P=0.001), NAFLD activity score (r=-0.473, P=0.026), and fibrosisstage (r=-0.719, P=0.001). Compared with NAFL, NASH patients had significantly lower %dose/h and %cumulative dose at 60, 90, and 120 minutes (always P<0.04) by C-ABT. C-ABT %dose/h and %cumulative dose at 120 minutes could predict the presence of NASH (area under the receiver operating characteristic curve: 0.762 and 0.741, respectively). In contrast, there was no significant association between C-GBT results and any patient characteristic.

CONCLUSIONS: In the NAFLD patients, decreased and delayed liver microsomal function, as assessed by C-ABT, is associated with more severe necroinflammation and fibrosis, whereas C-ABT results at 120 minutes may be helpful for the diagnosis of NASH.

PMID: 24335903 [PubMed - in process]

Source

Daclatasvir: The First of a New Class of Drugs Targeted Against Hepatitis C Virus NS5A

Curr Med Chem. 2013 Dec 28. [Epub ahead of print]

Gentile I, Borgia F, Coppola N, Buonomo AR, Castaldo G, Borgia G.

Abstract

Hepatitis C virus (HCV) infection affects about 160 million people worldwide. It is treated with pegylated-interferon (peg-IFN) and ribavirin, and in the case of patients affected by genotype 1, also with a protease inhibitor (telaprevir or boceprevir). Despite a good success rate, IFN-based combinations are contraindicated in several patients (e.g. decompensated cirrhosis, patients with psychiatric disorders, severe heart diseases or autoimmune disorders) and are associated with frequent adverse events that ultimately reduce their use. Numerous oral drugs are in an advanced phase of clinical development, and in some cases, in IFN-free combinations. This review focuses on preclinical and clinical data regarding daclatasvir (BMS-790052), which is a highly selective HCV NS5A replication complex inhibitor effective against HCV genotypes 1, 2, 3 and 4. In vitro data show that daclatasvir exerts a very potent antiviral effect against several HCV genotypes. Its pharmacokinetics is optimal and allows once-a-day oral administration. Its adverse event profile is good. Clinical data regarding its efficacy in combination with peg-IFN, ribavirin or other direct antiviral agents are impressive (rates of sustained virological response range between 60% and 100% in treatment-naïve patients). The only drawback of this drug appears to be a relatively low genetic barrier to resistance. In conclusion, daclatasvir, especially in combinations with other antiviral agents, is a very promising drug for the treatment of chronic hepatitis C.

PMID: 24372205 [PubMed - as supplied by publisher]

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Risk of transmission associated with sharing drug injecting paraphernalia: analysis of recent hepatitis C virus (HCV) infection using cross-sectional survey data

J Viral Hepat. 2014 Jan;21(1):25-32. doi: 10.1111/jvh.12117. Epub 2013 May 28.

Palmateer N, Hutchinson S, McAllister G, Munro A, Cameron S, Goldberg D, Taylor A.

Abstract

Sharing injecting paraphernalia (containers, filters and water) poses a risk of transmitting the hepatitis C virus (HCV). The prevalence of, and risk of HCV from, such behaviour has not been extensively reported in Europe. People who inject drugs (PWID) were recruited in cross-sectional surveys from services providing sterile injecting equipment across Scotland between 2008 and 2010. Participants completed a questionnaire and provided a blood spot for anonymous testing. Logistic regression was used to examine the association between recent HCV infection (anti-HCV negative and HCV-RNA positive) and self-reported measures of injecting equipment sharing in the 6 months preceding interview. Twelve per cent of the sample reported sharing needles/syringes, and 40% reported sharing paraphernalia in the previous 6 months. The adjusted odds ratios (AOR) for sharing needles/syringes (+/- paraphernalia), and sharing only paraphernalia in the last 6 months were 6.7 (95% CI 2.6-17.1) and 3.0 (95% CI 1.2-7.5), respectively. Among those who reported not sharing needles/syringes, sharing containers and filters were both significantly associated with recent HCV infection (AOR 3.1, 95% CI 1.3-7.8 and 3.1, 95% CI 1.3-7.5, respectively); sharing water was not. We present the first study to apply a cross-sectional approach to the analysis of the association between sharing paraphernalia and incident HCV infection and demonstrate consistent results with previous longitudinal studies. The prevalence of paraphernalia sharing in our study population is high, representing significant potential for HCV transmission.

© 2013 John Wiley & Sons Ltd.

KEYWORDS:

cross-sectional, hepatitis C, incidence, injecting paraphernalia, needles/syringes

PMID: 24329854 [PubMed - in process]

Source

Revisiting predictors of virologic response to PEGIFN + RBV therapy in HIV-/HCV-coinfected patients: the role of metabolic factors and elevated GGT levels

J Viral Hepat. 2014 Jan;21(1):33-41. doi: 10.1111/jvh.12118. Epub 2013 Aug 1.

Mandorfer M, Reiberger T, Payer BA, Breitenecker F, Aichelburg MC, Obermayer-Pietsch B, Rieger A, Puoti M, Zangerle R, Trauner M, Peck-Radosavljevic M.

Abstract

Evaluation of metabolic factors and elevated γ-glutamyltransferase (GGT) levels as independent predictors of treatment failure in a thoroughly documented cohort of HIV-/HCV-coinfected patients (HIV/HCV). Sixty-four HIV/HCV patients treated with pegylated interferon-α-2a plus ribavirin (PEGIFN + RBV) at the Medical University of Vienna within a prospective trial were included in this study. In addition, 124 patients with HIV/HCV from the AIFA-HIV and AHIVCOS cohorts were included as a validation cohort. Advanced liver fibrosis, GGT elevation, insulin resistance (IR) and low CD4+ nadir were defined as METAVIR F3/F4, GGT levels >1.5× sex-specific upper limit of normal, homoeostasis model assessment of insulin resistance >2 and CD4+ nadir <350 cells/μL, respectively. HCV-genotype 1/4 (OR26.3; P = 0.006), advanced liver fibrosis (OR20.2; P = 0.009), interleukin 28B rs12979860 non-C/C SNP (OR8.27; P = 0.02) and GGT elevation (OR7.97; P = 0.012) were independent predictors of treatment failure, while both IR (OR3.51; P = 0.106) and low CD4 + nadir (OR2.64; P = 0.263) were not independently associated with treatment failure. A statistically significant correlation between GGT elevation and prior alcohol abuse (r = 0.259; P = 0.039), liver steatosis (r = 0.301; P = 0.034) and low-density lipoprotein-cholesterol (r = -0.256; P = 0.041) was observed. The importance of GGT elevation as an independent predictor of treatment failure was confirmed in a validation cohort (OR2.76; P = 0.026). While GGT elevation emerged as an independent predictor of treatment failure in both the derivation and the validation cohort, no independent associations between metabolic factors and treatment failure were observed. Thus, our findings suggest that GGT elevation is an independent predictor of treatment failure in HIV/HCV that can easily be incorporated into predictive algorithms.

© 2013 John Wiley & Sons Ltd.

KEYWORDS: hepatitis C virus, human immunodeficiency virus, pegylated interferon, ribavirin, γ-glutamyltransferase

PMID: 24329855  [PubMed - in process]

Source

Relapse of 'Cured' HIV Patients Spurs AIDS Science On

Reuters Health Information

January 02, 2014

By Kate Kelland

LONDON (Reuters) Jan 02 - Scientists seeking a cure for AIDS say they have been inspired, not crushed, by a major setback in which two HIV-positive patients believed to have been cured experienced viral rebound.

True, the news hit hard last month that the so-called "Boston patients" - two men who received bone marrow transplants that appeared to rid them completely of HIV had relapsed and gone back onto antiretroviral treatment.

But experts say the disappointment could lay the basis for important leaps forward in the search for a cure.

"It's a setback for the patients, of course, but an advance for the field because the field has now gained a lot more knowledge," said Dr. Steven Deeks, a professor and HIV expert at the University of California, San Francisco.

He and other experts say the primary practical message is that current tests designed to detect even very low levels of HIV are simply not sensitive enough.

As well as being infected with HIV, the Boston patients both also had lymphoma for which they underwent bone marrow transplants - one man in 2008 and the other in 2010.

They continued taking antiretroviral drugs, but eight months after each patient's transplant, doctors found they could not detect any sign of HIV in their blood.

In the early part of 2013, both patients decided to stop taking their AIDS drugs and both appeared to remain HIV-free - prompting their doctors, Dr. Timothy Henrich and Dr. Daniel Kuritzkes from Boston's Brigham and Women's Hospital, to announce at a conference in July that they may have been cured.

Yet in December came news that one of the men had begun to show signs of an HIV rebound by August, while the second patient had a relapse in November.

Henrich said the virus' comeback underlined how ingenious HIV can be in finding hiding places in the body to evade attack efforts by the immune system and by drug treatment.

"Through this research we have discovered the HIV reservoir is deeper and more persistent than previously known and that our current standards of probing for HIV may not be sufficient," he said, adding that both patients were "currently in good health" and back on antiretroviral therapy.

INSPIRATION

Barely a decade ago, few AIDS researchers would have dared put the words HIV and cure in the same sentence. Yet some intriguing and inspiring cases in recent years mean many now believe it is just a question of time before a cure is found.

First was the now famous case of Timothy Ray Brown, the so-called "Berlin patient," whose HIV was eradicated by a complex treatment for leukemia in 2007 involving the destruction of his immune system and a stem cell transplant from a donor with a rare genetic mutation that resists HIV infection.

Such an elaborate, expensive and life-threatening procedure could never be used as a broad-spectrum approach for the world's 34 million HIV patients. But the results in Brown focused scientific attention on a genetic mutation known as CCR5 delta 32 as a target for possible gene therapy treatment.

Then last March, French scientists who followed 14 HIV-positive people known as the "Visconti patients," who were treated very swiftly with HIV drugs but then stopped treatment, said that even after seven years off therapy, they were still showing no signs of the virus rebounding.

That announcement came only weeks after news of the "functional cure" of an HIV-positive baby in Mississippi who received antiretroviral treatment for 18 months from the day she was born. By the time she was two this appeared to have stopped the virus from replicating and spreading.

A "functional cure" is when HIV is reduced to such low levels that it is kept at bay even without treatment, though the virus can still be detected in the body.

Sharon Lewin, an HIV expert at Monash University in Australia, said all these developments, as well as the setback suffered by the Boston patients, inspired scientists to investigate many different approaches in the search for a cure.

"We've learnt many things here - and one of the most important is that a tiny, tiny amount of virus can get the whole thing going again," she told Reuters. "It's a clear message that we need better ways to pick up the virus."

Scientists are now more convinced than ever that a two-pronged approach which aims to firmly suppress the virus while bolstering the immune system provides the best way forward.

"We need to attack in two ways - reduce the virus to very low levels and also to boost the immune response. We can't do one without the other," said Lewin.

"So we still have to think of other creative ways to control HIV. And it's still early days . . . before we can say which approach is likely to be the winner."

Source

Accuracy of physician reporting in routine public health surveillance for hepatitis C virus infection

Public Health Rep. 2014 Jan;129(1):64-72.

Jochem K¹, Leclerc P², Maurais E¹, Tremblay C¹, Cox J³.

Abstract

OBJECTIVE: From January 2007 to December 2008, the Montréal Public Health Department sent postal questionnaires to physicians and conducted patient interviews for all those newly diagnosed with hepatitis C virus (HCV) infection. We evaluated physician responses to risk factor questions for non-acute HCV cases.

METHODS: We compared physician and patient responses with each of nine risk factor questions, determined the sensitivity and specificity of physician responses compared with patient responses, and evaluated agreement using Gwet's agreement coefficient (AC1). We ranked risk factors and compared the distributions by principal exposure category according to physician reporting vs. patient interview using the Chi-square test.

RESULTS: The completeness of physicians' responses (yes, no, or unknown) varied by risk factor question from 90.8% to 96.7%. For risk factors present among more than 5% of cases, sensitivity of physician responses ranged from 26.9% to 87.7% and specificity ranged from 93.0% to 98.6%. The AC1 coefficients for agreement between physician and patient responses to lifetime risk factors considered most important in HCV acquisition were 0.80 for injection drug use, 0.95 for blood transfusion before 1990, and 0.86 for birth in a country with high HCV prevalence. Risk distributions by principal exposure category according to physician reporting vs. patient interview were not statistically different (χ(2)[4] = 2.17, p=0.704).

CONCLUSION: Postal questionnaires completed by physicians appear valid for determining the principal exposure category among non-acute HCV cases. Physician reporting can be a useful and low-cost component of routine HCV surveillance.

PMID: 24381361 [PubMed - in process]

Source

Treating HCV in HIV 2013: on the cusp of change

Liver International

Special Issue: Proceedings of the 7th Paris Hepatitis Conference International Conference of the Management of Patients with Viral Hepatitis, 13–14 January 2014, Paris, France. Guest Editors: Patrick Marcellin and Tarik Asselah. The publication of this supplement was supported by an unrestricted educational grant from Gilead, Janssen Therapeutics, Janssen, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Merck, AbbVie, Novartis, Idenix and Alios.

Volume 34, Issue Supplement s1, pages 53–59, February 2014

Review Article

You have free access to this content

Valérie Martel-Laferrière¹, Douglas T. Dieterich^2,*

Article first published online: 23 DEC 2013

DOI: 10.1111/liv.12396

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords:
co-infection;direct acting antiviral agents;hepatitis C; HIV

Abstract

Treating hepatitis C virus (HCV) in HIV/HCV co-infected patients is a challenge. Even if the benefits of achieving a sustained virological response are clear, the rates achieved with the combination of pegylated-interferon and ribavirin are disappointing. The addition of direct acting antiviral agents (DAAs) to the treatment of hepatitis C is revolutionizing the treatment of HCV in mono-infected patients. Even if there have not been any agents approved for the treatment of co-infected patients, many studies specifically designed for this population are ongoing. This article reviews available data on the use of DAAs in co-infected patients and the challenges associated with these new drugs.

Hepatitis C virus (HCV) co-infection is common in patients with HIV. Between 25 and 30% of HIV-infected patients are co-infected with HCV. Rates are even higher in populations where injection drug use is the principal mode of transmission of HIV.

Co-infected patients tend to have lower on-treatment sustained virological response (SVR) rates. SVR rates in the first trials of co-infected patients using pegylated-interferon (PEG-IFN) and fixed dose ribavirin (RBV), were 14–29% in genotype 1 and 44–73% in genotypes non-1 patients [1-3]. The use of weight-based RBV improved the rates to 36–38% in genotype 1 and 53–72% in genotype non-1 patients, which are still lower than the rates in mono-infected patients (40–60% in genotype 1 and 70–80% in genotypes 2 and 3 patients) [1, 4]. Nevertheless, co-infected patients can achieve a durable on-treatment SVR [5]. Like in mono-infected patients, the benefits of the reduction in fibrosis, liver decompensation and all causes of mortality are clear [6, 7].

The introduction of direct-acting antiviral agents (DAAs) has significantly improved the treatment outcomes in mono-infected patients [8]. No agents have been approved for co-infected patients. The scope of this article is to review the management of HCV in co-infected patients in the era of DAAs.

Pretreatment considerations

HIV treatment optimization

There are no absolute rules on the optimization of HIV before initiating HCV treatment. Although most co-infected patients who are treated for HCV are on antiretroviral therapy (ARV), this is not essential. In patients with an indication for HIV treatment, ARV should be initiated first with a regimen that does not have any drug–drug interactions with HCV antivirals. Some co-infected patients may present elevated transaminases when ARV are begun and may need to receive HCV treatment first.

Drug interactions

In the era of DAAs, drug–drug interactions are the biggest challenge that healthcare providers face in co-infected patients. For example, in our real-life study with telaprevir, 51.5% of co-infected patients had to change their HIV regimen before initiating HCV treatment to avoid drug–drug interactions [9]. This is often complex for the healthcare provider, especially in multiexperienced patients. A switch in HIV regimen can be emotionally difficult for the patient, who may fear losing control over HIV infection and developing new side effects.

No relevant drug–drug interactions have been found for sofosbuvir [10]. Telaprevir, boceprevir, faldaprevir and daclatasvir all act on the CYP3A [11-14]. Faldaprevir also inhibits CYP2C9 and UGT1A1 [14]. Simeprevir is an inhibitor of intestinal CYP3A and of CYP1A9 [15]. Boceprevir and daclatasvir are p-glycoprotein inhibitors [12, 13].

No clinically significant drug–drug interactions have been identified to date between tenofovir, emtricitabine and DAAs [11-15]. Abacavir is generally considered to be an acceptable choice even if potential interactions involving the UDP-gucuronyltransferase cannot be ruled out for telaprevir. Zidovudine, stavudine and didanosine are contraindicated with PEG-IFN/RBV and are therefore not acceptable options with the PEG-IFN/RBV-containing DAA regimens. Many interactions have been identified with non-nucleoside reverse transcriptase inhibitors. Efavirenz is contraindicated with boceprevir and simeprevir [12, 15]. It can be used with telaprevir, faldaprevir and daclatasvir, but dosages of DAAs must be increased (telaprevir: 1125 mg p.o. t.i.d.; faldaprevir: 240 mg p.o. OD; daclatasvir: 90 mg p.o. OD [15-17]. The integrase inhibitor raltegravir does not interact significantly with the telaprevir, boceprevir or simeprevir [15, 18, 19].

The HIV protease inhibitors (PI) are more complicated. Atazanavir boosted with ritonavir (/r) is considered to be an acceptable combination with telaprevir, while significant interactions have been noted for lopinavir/r, darunavir/r and fosamprenavir/r [20]. Even if they have been used in the phase II trials, PI should not be combined with boceprevir to avoid HIV escape [21]. Boceprevir reduces lopinavir/r, atazanavir/r and darunavir/r concentrations [22]. Although PI were tested in trials on daclatasvir and faldaprevir for co-infected patients, the dose of the DAA had to be reduced in both cases (daclatasvir: 30 mg p.o. OD; faldaprevir: 120 mg p.o. OD) [13, 14]. Darunavir/r is not recommended with simeprevir [15].

Evaluation of cirrhosis

Before initiating HCV treatment, it is important to identify if the patient has cirrhosis. Currently PEG-IFN-based regimens are contraindicated in patients with decompensated cirrhosis. Treatment can be attempted in patients with compensated cirrhosis but the patient's medical condition should be optimized first. Cirrhosis should be managed with regular procedures such as screening for hepatocellular carcinoma and oesophageal varices. Historically, didanosine use, bilirubin above the normal limit and pre-existent cirrhosis have been associated with a higher risk of liver decompensation in the treatment of co-infected patients [23]. The CUPIC study evaluated the outcome of mono-infected patients with cirrhosis treated with telaprevir or boceprevir in an early access program. This study found that low albumin (<35 g/dl) and low platelet count (≤100 000 cells/mm³) were associated with a significantly increased risk of severe on treatment complications or death [24]. Patients at risk of decompensation should be transferred to a liver transplant centre before beginning treatment of HCV. Criteria for liver transplantation in patients with HIV are much stricter than those for patients without, and not all transplant centres offer liver transplantation to patients with HIV.

SVR12 vs. SVR24

The Food and Drug Administration (FDA) has recently accepted a SVR at post-treatment week 12 (SVR12) as a primary outcome for clinical trials instead of the previously used SVR24 [25]. In a large cohort of HCV mono-infected patients treated with PEG-IFN/RBV therapy, it has been demonstrated that 12 weeks post-treatment follow-up appears to be as relevant as 24 weeks to define SVR [26]. Even if the data are limited, this new outcome also seems to be acceptable in co-infected patients. A retrospective analysis of the results of APRICOT and PARADIGM have shown that only 2/941 patients treated with combination IFN or PEG-IFN/RBV relapsed between post-treatment weeks 12 and 24 [27].

Table 1. Direct-acting antiviral agents (DAAs) in phase II or III trials

The phase IIa study VX08-950-110 included 60 co-infected patients naïve to HCV treatment [28]. Thirty-eight patients were in the telaprevir/PEG-IFN/RBV arm and 22 were in the placebo/PEG-IFN/RBV arm. Acceptable HIV regimens for this study were ATZ/r or efavirenz based regimens. If efavirenz was used, the dose of telaprevir was increased to 1125 mg three times daily. SVR rates were 74% in the telaprevir arm and 45% in the placebo arm. Although this is a small study, it is interesting to note that the SVR in the telaprevir arm was significantly higher than the historical SVR rates in co-infected patients with PEG-IFN/RBV and was very similar to the SVR rates observed in phase III telaprevir trials for mono-infected patients (75 and 72%) [32, 33]. As expected, side effects included rash and anorectal symptoms, but there was no statistically significant difference in anaemia. Adverse events were not more frequent in co-infected than in mono-infected patients. Phase III trials in co-infected patients are underway and results are expected in 2014 (NCT01513941 and NCT01467479) [31]. Real-life study results are now available for telaprevir-based therapy in co-infected patients. Cachay et al. has reported that 50% of 24 consecutive co-infected patients treated with telaprevir achieved a SVR [34]. In our study of 33 consecutive co-infected patients treated at Mount Sinai Medical Centre or Johns Hopkins University, 60.6% of patients achieved a SVR [9]. Previous non-responders were included in both cases, explaining in part the lower rate of SVR compared with the clinical trial. Nevertheless, SVR rates were clearly higher than those seen in PEG-IFN/RBV trials.

Careful management of mono- and co-infected patients on telaprevir-based therapy is mandatory to avoid, or at least to limit, severe adverse events. Since the approval of telaprevir, the FDA has modified the package insert to add medical visits to monitor haemoglobin and has added a black-box warning noting the association of telaprevir and cases of Stevens–Johnson syndrome [35]. In the study by Cachay et al., 50% of the patients developed grade IV adverse events according to the Division of AIDS criteria and 29% discontinued therapy because of side effects [34]. In our experience, 24.2% of our co-infected patients discontinued treatment because of side effects, but this was not statistically different than the discontinuation rate in mono-infected patients (13.8%, P = 0.18) [9]. Similarly, hospitalization rates (24.4% vs. 15.5%, P = 0.24) and severe anaemia (45.5% vs. 58.6%, P = 0.18) were elevated, but were not higher in co-infected than in mono-infected patients.

Boceprevir

Like telaprevir, boceprevir is an NS3/NS4A protease inhibitor with activity against HCV genotype 1. It is administered three times per day with food but with no fat requirements. The boceprevir treatment schedule is more complex than the telaprevir schedule with treatment varying from 28 to 48 weeks depending on the patient's previous response to PEG-IFN/RBV, his/her current response to the boceprevir-based regimen and the presence or absence of cirrhosis. There is an initial lead-in phase of 4 weeks with PEG-IFN/RBV before beginning boceprevir in all patients. The most common side effects are anaemia and dysgueusia.

The phase IIa boceprevir trial for co-infected patients was designed for naïve patients [21]. Sixty-four patients were enrolled in the boceprevir group and 34 in the placebo group. After a 4-week PEG-IFN/RBV lead-in, boceprevir or placebo was added for 44 weeks. Patients in the placebo group who failed at week 24 were offered boceprevir/PEG-IFN/RBV for an additional 44 weeks (crossover). Patients receiving didanosine, zidovudine or a non-nucleoside reverse transcriptase inhibitor were excluded. The SVR in the boceprevir group was significantly better than in the placebo group (62.5% vs. 29.4%, respectively, P < 0.01). Four patients were included in the crossover arm and three achieved SVR. Although almost all patients in both arms presented with treatment related adverse events, adverse events by symptom were more common in the boceprevir arm. On the other hand, there was no statistically significant difference in the rate of serious adverse events and treatment discontinuations because of adverse events between the two groups. Seven patients had an on-treatment HIV breakthrough, three (5%) in the boceprevir arm and four (12%) in the placebo arm. All these patients were on a HIV PI-based regimen, but this was also true for 86% of the boceprevir group and 91% of the placebo group. A phase III trial, sponsored by the National Institute of Allergy and Infectious Diseases, is underway [31].

Simeprevir

Simeprevir will probably be the next PI approved by the FDA because the New Drug Application of this agent has already been submitted[36]. The administration schedule of simeprevir is similar to that for telaprevir: triple therapy in combination with PEG-IFN/RBV followed by PEG-IFN/RBV alone for 24–48 weeks. Compared with boceprevir and telaprevir, this agent has a broader antiviral activity by genotype (genotypes 1 and 2, 4–6) and seems to be associated with fewer side effects (only transient hyperbilirubinaemia) [37].

Preliminary results of the C212 study were presented at the 2013 Conference on Retroviruses and Opportunistic Infections (CROI) [29]. This phase III study was designed for co-infected patients with any type of previous treatment response. All patients received 12 weeks of simeprevir. Naïve or relapser patients without cirrhosis were treated with PEG-IFN/RBV for 24 vs. 48 weeks depending on the virological response while patients with cirrhosis and previous partial or non-responders received 48 weeks of PEG-IFN/RBV. The ARVs abacavir, tenofovir, emtricitabine, lamivudine, raltegravir, rilpivirine, maraviroc and enfuvirtide were allowed. Overall, 106 patients were enrolled in this study. On-treatment week 4 results are available for 104: 66% of the patients were undetectable. As seen in many mono-infected trials, relapse patients had the best response rates (93%) while the rate in non-responders was 37%. SVR4 and SVR12 rates were presented for the subset of patients eligible for 24-week of treatment. Eighty-six percent of these 35 patients achieved SVR4 (naïve: 84%, relapsers: 90%) and 77% achieved SVR12 (naïve: 75%, relapsers: 80%). No HIV virological failure was reported.

Faldaprevir

Faldaprevir is the fourth PI to provide available data in co-infected patients. The optimal dosing and duration of therapy are still under evaluation in the phase III program (STARTVerso 1–4) [31]. The most common side effects associated with faldaprevir are gastrointestinal symptoms, rash and hyperbilirubinaemia [38].

STARTVerso 4 is the phase III program testing faldaprevir in co-infected patients [30]. This trial included naïve and relapse patients. Acceptable HIV non-nucleoside reverse transcriptase inhibitors were raltegravir, maraviroc, efavirenz, atazanavir/r and darunavir/r. Two doses were tested in this study (120 and 240 mg). To manage potential drug–drug interactions, patients receiving efavirenz were assigned to the 240 mg group while patients receiving darunavir/r or atazanavir were assigned to the 120 mg group. Patients receiving maraviroc or raltegravir were randomized. A total of 308 patients were included in this study, including 17% with cirrhosis. This study design of STARTverso 4 is complex and is presented in Fig. 1. Preliminary on-treatment results were presented at CROI 2013. At week 12 of treatment, 82% of the previously naïve patients and 91% of the previous relapsers had undetectable viral loads.

Figure 1. STARTverso 4 design. pegIFN, pegylated-interferon; RBV, ribavirin; die, once a day.

Of interest, faldaprevir has been tested in combination with deleobuvir, a non-nucleosidic NS5B inhibitor, and RBV for the treatment of HCV mono-infected patients [39]. There were five arms in this phase IIb trial to explore the impact of the length of treatment, the use of ribavirin and the administration schedule (two vs. three times daily) of deleobuvir. SVR was achieved by 52–69% of the patients [39]. The combination is currently being studied in co-infected patients (NCT01525628) [31].

Daclatasvir

Daclatasvir is an NS5A inhibitor with activity against HCV genotype 1. It is administered once daily at a dose of 60 mg, which may be adjusted to 30 or 90 mg when combined with an HIV protease inhibitor or efavirenz respectively. Daclatasvir has been studied in combination with many agents including PEG-IFN, RBV, sofosbuvir and asunaprevir. A phase III trial in co-infected patients is ongoing (NCT01471574) [31]. It was designed to include HCV genotype 1 naïve patients. Daclatasvir will be administered for 24 weeks and PEG-IFN/RBV for 24 vs. 48 weeks depending on virological response criteria for shorter therapy.

Sofosbuvir

Sofosbuvir is a nucleotide NS5B polymerase inhibitor [40]. It is administered once daily at a dose of 400 mg. Sofosbuvir is a pangenotypic agent and no specific side effects have been identified. It will probably be the first non-PI DAA approved because its New Drug Application Form was submitted to the FDA in the Spring of 2013 [41]. Mono-infected patients with HCV genotypes 1, 4–6, receive sofosbuvir in combination with PEG-IFN and RBV for 12 weeks [40]. Patients with genotypes 2 and 3 receive an interferon-free combination with RBV alone [40, 42]. Two phase III trials (NCT01667731 and NCT01783678) are ongoing [31]. One study includes patients with genotypes 1–3 and the other 1–4. Interestingly, these two studies are interferon-free even in patients with genotype 1 or 4.

Acute hepatitis C and DAAs

Because of the development of new drugs for the treatment of chronic HCV, little attention is being paid to acute hepatitis C. Nevertheless, this condition is still a major health issue, especially in patients with HIV. Sexual transmission of HCV in HIV-infected patients is now well-recognized, with outbreaks described worldwide.

The European AIDS Treatment Network (NEAT) currently recommends the use of PEG-IFN and weight-based RBV for the treatment of acute HCV in HIV-infected patients. Twenty-four weeks of treatment is recommended for patients who achieve a rapid virological response (undetectability at week 4; RVR). Other patients should be treated for 48 weeks and patients who do not present a 2 log₁₀ drop at week 12 should discontinue treatment because the probably will not achieve a SVR. NEAT recommends beginning treatment in patients with persistent HCV RNA 12 weeks after diagnosis or if a 2 log₁₀ decrease in HCV RNA does not occur 4 weeks after the initial HCV RNA [43]. The EASL and AASLD do not have specific guidelines for acute HCV in co-infected patients.

As expected from results in acute vs. chronic monoinfected patients, co-infected patients with acute HCV tend to have better SVR rates than those with chronic infection. Rates in published trials vary from 53 to 82% [44, 45]. Very little information is available on DAAs in the treatment of acute HCV. Fierer presented the preliminary results of a small study with telaprevir at CROI 2013. Eighty-five per cent (17/20) patients treated with 12 weeks of PEG-IFN/RBV and telaprevir achieved SVR4 [46].

Conclusions

Studies clearly show that DAAs will change the face of treatment in patients with HIV/HCV coinfection. These new agents seem to fill in the gap in treatment outcomes between co- and mono-infected patients. Adverse events with telaprevir and boceprevir must be managed, but do not appear to be more important in co-infected patients and side effect profiles, at least for haematological effects will probably be less severe.

Drug–drug interactions are a real issue. Compatible options of ARV and antiviral combinations are limited. This review only discussed trials on co-infection with available or soon to be available data. In the up-coming era of an interferon-free regimen, treatment will probably combine many DAA's, increasing the chance of drug–drug interactions.

Another potential issue in the management of co-infected patients will be access to treatment. Specific approval by agencies such as the FDA, European Medicine Agency or Health Canada for this population will be required to insure reimbursement of drugs by insurance companies.

Disclosure

Valérie Martel-Laferrière has nothing to disclose. Douglas T. Dieterich serves as a paid lecturer, consultant and for his service on scientific advisory boards for Gilead Sciences, Boehringer Ingelheim, Novartis, Vertex Pharmaceuticals, Achillion, Tibotec, Merck, Genentech and Hoffman-La Roche, Inc. and Bristol-Myers Squibb.

References

Source

FG inaugurates technical group on hepatitis disease control

Thursday, 02 January 2014 00:00 Written by From: Emeka Anuforo

THE Federal Government has inaugurated a Technical Working Group on viral Hepatitis Control in Nigeria, as a quick intervention on the increasing burden of hepatitis virus in the country.

The government has also bemoaned the dearth of attention given to the control of the infection globally.

Minister of Health, Onyebuchi Chukwu, said at the inauguration of the working group in Abuja that hepatitis was much dangerous than the HIV/AIDS, and as such, required significant national attention.

Meanwhile, a survey carried out by the Nigeria Centre for Disease Control, supported by Roche Pharmaceuticals, finds that Nigeria has 11 per cent hepatitis B prevalence and little over 2.2 per cent Hepatitis C prevalence.

Sub-Saharan Africa, among other regions, is considered to be the most endemic, with average carrier rate of 10-20 per cent in general population.

But, while hepatitis B has vaccines for prevention, there is no vaccine currently available for against hepatitis C.

Chukwu said the Federal Government was prepared to bring the issue of hepatitis to the front burnåer.

He said: “More than two billion people are infected with hepatitis B virus world wide while some 280 million are chronic carriers, having the virus in their liver. About two million of these carriers die each year as a result of liver cirrhosis or primary liver cell cancer induced by the virus.

“Unfortunately, not much attention has been given to hepatitis control globally and especially in Nigeria even when the burden of hepatitis is rapidly increasing and progress could be effectively prevented.

“Globally about 34 million people are infected with Human Immunology Deficiency Virus (HIV) compared with 400 million persons infected with the hepatitis virus.

“HIV attracts funding of about $2,774/person living with HIV annually while only about $20 is spent per viral hepatitis patient.”

Represented, by the Permanent Secretary, Amb. Sani Bala, he noted that the Technical working Group was government response to curbing the menace.

The Minister stressed that the group would come up with articulated and cost effective framework for viral hepatitis control for Nigeria.

The committee’s terms of reference includes providing technical guidance for implementation of hepatitis control programme within existing policies and plans; to support advocacy and resource mobilisation efforts for hepatitis prevention, management and control; to support the ministry in the development of the national guideline on hepatitis prevention, management and control in Nigeria; and to explore ways and means of making innovative partnership towards making the prevention of hepatitis a national priority.

He noted that more than two billion people were infected with hepatitis B Virus globally while about 280 million are chronic carriers, having the virus in their liver.

About two million of these carriers, he said, die each year as a result of liver cirrhosis or primary liver cell cancer induced by the virus. Sub-Saharan Africa, the Minister stated, is considered to be a high endemic region, with an average carrier rate of 10 – 20 percent in the general population.

“Globally, about 34 million people are infected with the Human Immunodeficiency Virus (HIV) compared with 400 million persons infected with the hepatitis virus.

“HIV attracts funding of about $2,774/Person Living With HIV annually, while only about $20 is spent per viral hepatitis patient. A recent survey conducted by the Nigeria Centre for Disease Control supported by Roche Pharmaceuticals showed that Hepatitis B & C viruses have prevalence of 11.0 per cent and 2.2 per cent respectively. While there is a vaccine for the prevention of Hepatitis B, there is no vaccine currently available for vaccination against the Hepatitis C infection.”

Source

Prevention of hepatocellular carcinoma in chronic viral hepatitis B and C infection

World J Gastroenterol. 2013 December 21; 19(47): 8887-8894.

Published online 2013 December 21. doi: 10.3748/wjg.v19.i47.8887.

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

Tao Lu, Wai-Kay Seto, Ran-Xu Zhu, Ching-Lung Lai and Man-Fung Yuen.

Tao Lu, Wai-Kay Seto, Ran-Xu Zhu, Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China

Wai-Kay Seto, Ching-Lung Lai, Man-Fung Yuen, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Author contributions: Lu T and Seto WK did the literature search and wrote the manuscript; Zhu RX did the literature search and reviewed the manuscript; Lai CL reviewed the manuscript; Yuen MF designed the manuscript topic, reviewed the manuscript and supervised the study.

Correspondence to: Man-Fung Yuen, MD, PhD, Professor, Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. mfyuen@hkucc.hku.hk

Telephone: +86-852-22553984 Fax: +86-852-28725828

Received September 10, 2013; Revised October 26, 2013; Accepted November 12, 2013;

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with the majority of cases associated with persistent infection from hepatitis B virus (HBV) or hepatitis C virus (HCV). Natural history studies have identified risk factors associated with HCC development among chronic HBV and HCV infection. High-risk infected individuals can now be identified by the usage of risk predictive scores. Vaccination plays a central role in the prevention of HBV-related HCC. Treatment of chronic HBV infection, especially by nucleoside analogue therapy, could also reduce the risk of HBV-related HCC. Concerning HCV infection, besides the advocation of universal precautions to reduce the rate of infection, pegylated interferon and ribavirin could also reduce the risk of HCV-related HCC among those achieving a sustained virologic response. Recently there has been mounting evidence on the role of chemopreventive agents in reducing HBV- and HCV-related HCC. The continued advances in the understanding of the molecular pathogenesis of HCC would hold promise in preventing this highly lethal cancer.

Keywords: Hepatitis B virus, Hepatitis C virus, Hepatocellular carcinoma, Vaccination, Prevention

Core tip: Hepatocellular carcinoma (HCC), with the majority of cases associated with infection from hepatitis B virus (HBV) or hepatitis C virus (HCV), is the most common primary liver tumor. We introduced risk factors and risk predictive scores associated with HCC development among chronic HBV and HCV infection for its early diagnose and prevention. Vaccination plays a central role in the prevention of HBV-related HCC. Treatment of chronic HBV infection, especially by nucleoside analogue therapy, could reduce the risk of HBV-related HCC. Pegylated interferon and ribavirin could reduce the risk of HCV-related HCC. Chemopreventive agents in reducing HBV- and HCV-related HCC were also discussed.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common primary liver tumor, and represents the third leading cause of cancer death worldwide. It is the fifth most common cancer in men and seventh in women, accounting for 7% of all cancers[¹]. Hepatocarcinogenesis is a multistep process mainly associated with persistent infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)[²], which affects more than 350 and 170 million individuals respectively worldwide. HCC is highly prevalent in regions endemic for chronic HBV and HCV infection[³].

The incidence of HCC continues to increase worldwide, with a unique geographic, age, and sex distribution. The most important risk factor associated with HCC is liver cirrhosis, which is again predominantly caused by chronic HBV or HCV infection. Primary prevention in the form of HBV vaccination has led to a significant decrease in HBV-related HCC, and the antiviral therapy for chronic HBV and HCV infection also reduce the incidence of HBV- and HCV-related HCC[⁴].

China has one of the highest carrier rates of HBV in the world，reaching nearly 10% of the general population. The disease burden of HBV infection and HCC is also believed to be among the world’s largest, and that of HCV infection is likely to be substantial as well[⁵].

RISK PREDICTION

An important component of HCC prevention is the identification of high-risk HBV- and HCV-infected individuals, who will benefit from various chemopreventive therapies discussed below. Several natural history studies have identified important risk factors for HCC among patients with chronic hepatitis B (CHB) and chronic hepatitis C (CHC), with risk predictive scores also designed for practical usage.

Risk factors and prediction scores: CHB

A study evaluating the relationship between serum HBV DNA level and risk of HCC demonstrated that the incidence of HCC among CHB patients increased with serum HBV DNA level. Elevated serum HBV DNA level (≥ 2000 IU/mL) is a strong risk predictor of HCC independent of hepatitis B e antigen (HBeAg)-positivity, serum alanine aminotransferase levels, and liver cirrhosis[⁶]. Subsequent studies also showed patients with moderate levels of serum HBV DNA (60-2000 IU/mL), when compared to individuals not infected with HBV, still had a substantial increased risk of HCC and liver-related death[⁷].

Besides serum HBV DNA levels, other host- and viral-related factors could also predispose to HCC. A meta-analysis found HBeAg-positive non-cirrhotic patients, when compared to HBeAg-positive cirrhotic patients, had a significantly reduced HCC risk after antiviral therapy[⁸]. HBV genotype also plays a role; HBV genotype C is closely associated with HCC especially in cirrhotic patients aged > 50 years[⁹]. An observation study in Hong Kong also found genotype C HBV infection to be an independent risk factor for HCC development when compared with genotype B[¹⁰].

Several clinical scoring systems have been developed for the prediction of HCC in CHB, as depicted in Table 1. These scoring systems are based on the longitudinal follow-up of treatment-naïve CHB patients for 5 years or more. Two common parameters used are age and serum HBV DNA levels. Other parameters used include gender, serum alanine aminotransferase levels, serum albumin, HBeAg status, presence of cirrhosis and presence of core promoter mutations[^11-15]. Risk prediction is now also possible for CHB patients undergoing nucleoside analogue (NA) therapy. A recent study investigated the risk of HCC among a large population of CHB patients treated with entecavir. Older age and presence of cirrhosis were independently associated with HCC in the entire cohort; advanced age and hypoalbuminemia were associated with HCC in patients without cirrhosis. The risk scores accurately predict which patients with CHB treated with entecavir would have a higher chance of developing HCC[¹³].

Table 1 Risk factors and prediction scores for hepatitis B virus- and hepatitis C virus-related hepatocellular carcinoma

Risk factors	HBV-related HCC	HCV-related HCC
Increased age	√[11-15]	√[16]
Male gender	√[11,12,15]	√[16]
Increased serum HBV DNA levels	√[11,12,14,15]
Presence of cirrhosis	√[12-14]
Increased serum ALT concentration	√[11,15]
HBeAg positivity	√[11,15]
Presence of core promoter mutations	√[12]
Presence of virological remission after 24 mo	√[13]
Presence of hypoalbuminemia	√[13]
Decreased serum albumin	√[14]
Increased serum bilirubin	√[14]
HBV genotype C	√[15]
Presence of HBsAg	√[15]
Family history of HCC	√[15]
Presence of portal hypertension		√[16]
Presence of hepatic inflammation		√[16]
Increased iron storage levels		√[16]
Presence of sustained virological response		√[17]
Presence of complete viral suppression		√[17]

HBV: Hepatitis B virus; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; HBsAg: Hepatitis B surface antigen; ALT: Alanine aminotransferase.

 

Risk factors: CHC

When compared to CHB, fewer clinical scoring systems have been developed for the prediction of HCV-related HCC. These are as depicted in Table 1. The majority of HCV-related HCC develop in patients with established cirrhosis. In a study investigating prognostic risk factors for HCV-related HCC, among 913 patients followed up for at least 3 years, age, male sex, portal hypertension, hepatic inflammation, and iron storage were significant risk factors for HCV-related HCC[¹⁶]. In a meta-analysis involving HCV-infected persons, sustained virologic response (SVR) was associated with reduced risk for HCC[¹⁷]. Even transient virologic control among patients with subsequent relapse after treatment, was associated with a lower risk of the development of HCC[¹⁸].

Prediction of HCV-related HCC may be enhanced by the development of related markers. Signal transducer and activator of transcription 1 and phosphatase and tensin homolog are associated with early growth response protein 1 signaling, which potentially promotes angiogenesis, fibrogenesis, and tumorigenesis in HCV-related HCC. This approach has potential for the early diagnosis and possible prevention of HCC. The corresponding serum markers found can help to predict high-risk groups for HCC[¹⁹].

Host factors

HCC is more common in HBV carriers with a family history of HCC. In a study of 5238 HBV carriers (553 with HCC and 4685 without HCC), the risk of HCC was significantly higher in those with a family history of HCC, with a multivariate-adjusted rate ratio for HCC of 2.41 compared with HBV carriers without a family history[²⁰]. If the carriers had two or more affected family members, the risk was even higher with the ratio increased to 5.55. It is therefore recommended to begin surveillance in adults once a family history of HCC has been identified. A recently published study also included the presence of family history, besides traditional viral-related parameters as a component for risk prediction[¹⁵].

PREVENTION OF HBV-RELATED HCC

HBV infection is the major cause of HCC. Vaccination against HBV is instrumental in the prevention of HCC, and is recommended for all newborns and individuals who are at increased risk for infection. Studies in Taiwan, where universal HBV vaccination was introduced in 1984, have documented a significant decrease in the incidence of HCC in both children and adolescents after the introduction of HBV vaccination as discussed below[^21,22].

In patients already chronically infected with HBV, antiviral treatment could prevent disease progression to cirrhosis or HCC. Additionally, periodic surveillance using ultrasonography and serum α-fetoprotein every 3-6 mo for earlier detection of HCC is also important so that curative treatments (e.g., hepatic resection) can be offered[²³].

The antiviral interventions and chemopreventive methods to prevent

Table 2 Antiviral interventions for prevention of hepatitis B virus- and hepatitis C virus-related hepatocellular carcinoma

Antiviral interventions	HBV-related HCC	HCV-related HCC
IFN: IFN-α	+/-[28,29]	√[46]
Pegylated IFN		√[47]
NAs: Lamivudine	√[36]
Entecavir	√[37,38]
Ribavirin		√[47]
Vaccination	√[21,22]
Screening of blood product	√[27]	√[27]

HBV: Hepatitis B virus; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; IFN: Interferon; NA: Nucleotide analogs.

Table 3 Chemopreventive agents for hepatitis B virus- and hepatitis C virus-related hepatocellular carcinoma

Chemopreventive agents	HBV-related HCC	HCV-related HCC
Statins	√[42]
Antidiabetic medications	√[42]	√[42]
Aspirin	√[41,53]	√[53]
Propranolol		√[51]
FASN		√[52]
Dietory agents: Coffee	√[54]	√[54]
Vitamin E	√[54]	√[54]
Vitamin D		√[50]
Fish oil (n-3 PUFA)	√[55-57]	√[55-57]
Phytochemicals: Resveratrol	√[43]
EGb	√[44]

HBV: Hepatitis B virus; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; PUFA: Polyunsaturated fatty acid; FASN: Fatty acid synthase; EGb: Extract of ginkgo biloba leaf.

Vaccination

Vaccination plays a central role in HBV prevention strategies worldwide, and a decline in the incidence and prevalence of HBV infection following the introduction of universal HBV vaccination programs has been observed in many countries[²⁴]. Control and significant reduction in incidence of new HBV infections as well as HCC have been repeatedly reported in countries in East Asia and Africa[²⁵].

A study of the incidence of HCC in children in Taiwan from 1981 to 1994 showed that the average annual incidence of HCC in children 6-14 years of age declined from 0.70 per 100000 children (between 1981 and 1986), to 0.57 per 100000 (between 1986 and 1990), and to 0.36 per 100000 (between 1990 and 1994). The corresponding rates of mortality from HCC had also decreased. The incidence of HCC in children 6-9 years of age declined from 0.52 per 100000 (for those born between 1974 and 1984) to 0.13 per 100000 (for those born between 1984 and 1986). Since the institution of Taiwan’s program of universal HBV vaccination from 1984, the incidence of HCC in children has declined dramatically[²²]. The risk of developing HCC for vaccinated cohorts was statistically significantly associated with incomplete HBV vaccination. The prevention of HCC by HBV vaccination extends from childhood to early adulthood. Failure to prevent HCC results mostly from unsuccessful control of HBV infection by highly infectious mothers[²¹].

Antiviral therapy: Interferon and NAs

DNA integration of hepatitis viruses alters the function of critical genes, promoting malignant transformation of virus-infected liver cells[²⁶]. Treatment of CHB infection aims to control viral replication and prevent the development of complications. There are currently seven drugs available for the treatment of CHB, five NAs and two interferon (IFN)-based therapies. Long-term treatment with NA is often required, and the decision to treat is based on the clinical assessment including the phase of CHB infection and the presence and extent of liver damage[²⁴].

Concerning IFN therapy, a study involving 641 biopsy-proven CHB patients treated with IFN-α2b were followed up for a median period of 113 months. Although HCC occurred less frequently in biochemical responders than in non-responders, virologic response is not associated with decrease in HCC development. Poor biochemical response, as well as older age and a higher serum AFP level remain independent predisposing factors of HCC development in CHB patients treated with IFN-α[²⁷]. In addition, a study about the long-term effects of IFN-α in Chinese patients showed that IFN-α was of no long-term benefit in inducing HBeAg seroconversion or in the prevention of HCC and other cirrhosis-related complications[²⁸].

On the contrary, nearly all the studies showed that NA is able to reduce HCC[²⁹]. Many randomized controlled trials showed that lamivudine, one of the earliest oral NAs for antiviral therapy in HBV infection, can reduce disease progression in HBV-related cirrhosis and HCC[^29-34]. A recent study followed up 293 CHB patients without HCC who were treated with lamivudine for a mean duration of 67.6 mo. In cirrhotic patients, the attainment of maintained viral response (defined as HBV-DNA levels of < 4.0 log copies/mL) during lamivudine treatment was revealed to reduce the risk of HCC development. No significant reduction was observed in the non-cirrhotic group[³⁵].

Entecavir is a potent NA with high genetic barrier to resistance, and prolonged treatment results in regression of fibrosis, hence is currently recommended as first-line antiviral therapy for CHB. In a study of CHB patients with liver cirrhosis, entecavir therapy reduces the risks of hepatic complications, HCC, liver-related and all-cause mortality of CHB patients with liver cirrhosis in 5 years, particularly among those who had sustained viral suppression[³⁶]. In another multicentre cohort study, 372 entecavir-treated patients followed up for a mean duration of 114 mo were investigated. Clinical events were defined as development of HCC, hepatic decompensation or death. Virological response to entecavir (HBV DNA < 80 IU/mL) was associated with a lower probability of disease progression in patients with cirrhosis, suggesting that complete viral suppression is essential for NA treatment, especially in patients with cirrhosis[³⁷].

A meta-analysis investigating the effects of IFN or NA on the risk of developing HCC in CHB patients shows that, the reduction in HCC is more significant among patients with early cirrhosis than among non-cirrhotic patients. Five studies (n = 2289) compared patients treated by NA with control. The risk of HCC after treatment is reduced by 78%. HBeAg-positive patients have a more significant reduction in HCC risk with treatment. Patients without cirrhosis benefit more from NA than those with cirrhosis, although resistance to NA blunts the benefit of treatment[⁸].

In summary, while the evidence of the efficacy of IFN in preventing HBV-related HCC remains conflicting, there is a gradual accumulation of evidence supporting the positive effect of NA on reducing HBV-related HCC.

Chemoprevention

The observation that anti-platelet therapy inhibits or delays immune-mediated hepatocarcinogenesis suggests that platelets may be one of the key players in the pathogenesis of HBV-associated liver cancer and that immune-mediated necroinflammatory reactions may be an important cause of malignant transformation during chronic hepatitis[³⁸]. A prospective study on 300504 patients with chronic liver disease showed that aspirin users had statistically significant reduced risks of incidence of HCC and mortality due to chronic liver disease compared to those who did not use aspirin[³⁹]. Further studies are needed to confirm this finding and clarify its underlying mechanism.

A study concerning the association between the use of statins in HBV-infected patients and the risk of HCC shows that statin use may reduce the risk for HCC in HBV-infected patients in a dose-dependent manner[⁴⁰]. This may be related to the effect of statins in reducing fatty change in the liver, and requires future validation studies to confirm the findings.

There are also several investigational drugs which could have potential for chemoprevention against HBV-related HCC. Resveratrol is a natural polyphenol that has beneficial effects across various disease models. In an animal study investigating the efficacy of resveratrol against HBV-related HCC in HBV X protein (HBx) transgenic mice, resveratrol had a pleiotropic effect on HBx transgenic mice in terms of the down-regulation of lipogenesis, the promotion of transient liver regeneration, and the stimulation of antioxidant activity. Furthermore, at later precancerous stages, resveratrol delayed HBx-mediated hepatocarcinogenesis and reduced HCC incidence from 80% to 15%. The potential mechanisms for resveratrol on HCC prevention might be associated with its effects of stimulating the activity of Ampk and SirT1, and downregulating the expression of the lipogenic genes, Srebp1-c and peroxisome proliferator-activated receptor gamma. The decrease in Srebp1-c further downregulates the expression of its target genes, Acc and Fas[⁴¹]. Several other studies demonstrated resveratrol downregulates cyclin D1 as well as p38 MAP kinase, suppresses Akt and Pak1 expression and activity, and increases ERK activity, suggesting that growth inhibitory activity of resveratrol is associated with the downregulation of cell proliferation and survival pathways, and sensitization to apoptosis[⁴²]. Resveratrol also acts as an inhibitor for sirtuins. Overexpression of SIRT1 in cancer tissue has been demonstrated to promote mitotic entry of liver cells, cell growth and proliferation, and inhibit apoptosis related to the PTEN/PI3K/AKT signaling pathway[^43,44].

A study in China suggested that extract of Ginkgo Biloba leaf (EGb) could reduce the incidence of the HCC with HBV transgenic mice. The reason may be that EGb could reduce liver HBx, p53, Bcl-2 protein expression in HBV transgenic mice[⁴⁵]. These investigational products would need confirmation in human clinical trials in the future.

PREVENTION OF HCC RELATED TO HCV

With the commencement of successful vaccination programs against HBV, CHC is now emerging as an important cause of chronic liver diseases. The drive of carcinogenesis during HCV infection is thought to result from the interactions of viral proteins with host cell proteins. Thus, the induction of liver mutation phenotypes through the expression of HCV proteins provides a key mechanism for the development of HCV-associated HCC. With the emerging importance of CHC, mechanisms of HCV-associated hepatocellular carcinogenesis should be clarified to provide insight into advanced therapeutic and preventive approaches to decrease the incidence and mortality of HCC[⁴⁶].

Strategies aimed at eliminating the virus may provide opportunities for effective prevention of the development of HCC. The first step is to encourage universal precautions to reduce infections transmittedvia different modalities e.g., iatrogenic routes, sharing of intravenous needles etc and further implementation of universal screening of donated blood products. Concerning therapy for HCV, pegylated IFN plus ribavirin therapy is effective at reducing the risk of HCC in patients with CHC who achieve SVR.

The effects of antiviral therapy and chemopreventive measures in preventing HCC are mentioned in Tables 2and 3 respectively.

Antiviral therapy: IFN and ribavirin

Current strategies to reduce HCC incidence in CHC patients include prevention of cirrhosis development by avoiding metabolic, pharmacological, or social factors associated with accelerated progression of liver disease, or through virus eradication by IFN-based treatments. Moreover, a successful antiviral treatment has positive impact on the rate of HCC development in patients who are already cirrhotic[¹].

Combination of pegylated IFN and ribavirin therapy is recommended for antiviral therapy worldwide, and is effective in reducing the rate of recurrence of HCV-associated HCC after curative resection or transplantation[⁴⁷]. The pooling of data from the literature suggests a preventive effect of antiviral therapy on HCC development in patients with HCV-related cirrhosis, but the preventive effect is limited to those achieving SVR[⁴⁸]. However, some HCV mutations, such as the amino acid substitution M91L, are associated with treatment failure and a poor prognosis[⁴⁷].

There is a recent study of the effect of pegylated IFN and ribavirin treatment of CHC on the incidence of HCC. After a median observation period of 3.6 years, a significantly lower rate of HCC incidence was noted in patients achieving SVR when compared to non-virological responders. A similarly lower rate of HCC incidence was noted among cirrhotic patients achieving SVR (18.9%) when compared to cirrhotic non-virological responders (39.4%)[¹⁸].

A meta-analysis study has been performed recently with the data sources from MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science, and the Database of Abstracts of Reviews and Effectiveness from inception through 2012, to systematically review observational studies to determine the association between response to HCV therapy and development of HCC among persons at any stage of fibrosis and those with advanced liver disease. Among HCV-infected persons, there is moderate-quality evidence demonstrating SVR to be associated with reduced risk for HCC; SVR after treatment among HCV-infected persons at any stage of fibrosis is associated with reduced HCC[¹⁷].

Chemoprevention

Vitamin D insufficiency has been associated with the occurrence of various types of cancer. A recent study aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing HCV-related HCC. The data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis[⁴⁹].

Propranolol has antioxidant, anti-inflammatory, antiangiogenic properties and antitumoral effects and therefore is potentially active in the prevention of HCC. A retrospective long-term observational study suggests that propranolol treatment might decrease HCC occurrence in patients with HCV cirrhosis[⁵⁰]. These findings also need to be verified by prospective clinical trials.

Understanding the interplay between the viral and cellular components of the HCV replication complex could provide new insight for prevention of the progression of HCV-associated HCC. Fatty acid synthase (FASN) is found to interact with NS5B. FASN may thereby serve as a target for the treatment of HCV infection and the prevention of HCV-associated HCC progression[⁵¹]. Thus, understanding the molecular mechanisms, which are implicated in the development of HCC during the course of HCV infection, may help to design a general therapeutic protocol for the treatment and for its prevention.

PREVENTION OF HCC RELATED TO HBV AND HCV COINFECTION

HBV and HCV coinfection is not uncommon with an estimated 7-20 million infected individuals worldwide[⁵²]. A community-based prospective cohort study evaluating HCC development in HBV and HCV co-infected subjects found the hazard ratios (HRs) of HBV monoinfection, HCV monoinfection, and HBV/HCV coinfection were 17.1, 10.4 and 115.0, respectively. Different genotypes and multiplicative synergistic effect of HBV and HCV coinfection on HCC risk was observed. Infection with HCV genotype 1 (HR = 29.7) and mixed infection with genotype 1 and 2 (HR = 68.7) significantly elevated HCC risk, much higher than HBV infection. The effect of different HCV genotypes and the multiplicative synergistic effect of HBV/HCV coinfection on HCC risk underline the need for comprehensive identification of hepatitis infection status in order to prevent and control HCC[⁵³].

Pegylated interferon-alpha plus ribavirin should be recommended in patients with dominant HCV replication. However, HBV rebound may occur after elimination of HCV with anti-HBV treatment required. These therapeutic measures may contribute to the prevention of HCC this special group of patients[⁵²].

OTHER POTENTIAL CHEMOPREVENTIVE METHODS

The use of aspirin, but not nonsteroidal anti-inflammatory drugs, is associated with a decreased risk of HCC and death from chronic liver disease in the National Institutes of Health-AARP Diet and Health Study of patients between the ages of 50 and 71 years[³⁹]. However this study does not provide information on the HBV and HCV status of its participants, and would need confirmation by future studies specifically for the HBV- and HCV-infected population.

More recent data have suggested dietary factors, including increased intake of coffee[⁵⁴], unsaturated fatty acids and fish to be protective against HCC. Subjects with known HBV or HCV status, and subjects who were anti-HCV and/or hepatitis B surface antigen positive were analysed. Consumption of n-3 polyunsaturated fatty acid (PUFA)-rich fish or n-3 PUFAs, particularly eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid, appears to protect against the development of HCC, even among subjects with HBV and/or HCV infection[⁵⁵], probably through dampening the inflammation in the liver and decreasing formation of tumor necrosis factor (TNF)-α, and through simultaneously inhibition of COX-2 and beta-catenin[^56,57]. The findings also point to a potential anticancer role for the n-3 PUFA-derived lipid mediators 18-HEPE and 17-HDHA, which can down-regulate the important proinflammatory and pro-liferative factor TNF-α.

CONCLUSION

Clinical experts evaluated ten previously identified dimensions of HCC control: clinical education; risk assessment; HBV strategy; HCV strategy; life-style risk factors; national statistics; funding for screening; funding for treatment; political awareness; and public awareness. Of these strategies, the most significant needs in regional efforts to control HCC are political awareness, public awareness, and life-style risk factors[⁵⁸].

HCC is a challenging malignancy of global importance. As HCC is strongly associated with chronic viral hepatitis, prevention against the infection is crucial for prevention against HCC. Vaccination against HBV in the newborns and early childhood is highly effective to lower infection rates substantially. For HCV, universal precautions when dealing with human blood, education on high-risk behaviours and screening programs for blood donors can reduce infection rates. Although prevention and treatment of CHB and CHC have been improved within the last decades even in high-risk countries, further effective and sustainable reduction of these infections is still needed[²⁶].

Antiviral therapies for CHB and CHC, while important, can only reduce but not completely eliminate HCC. Improvement in identification of infected persons, accessibility of care and affordability of treatment are needed for antiviral therapy to have a major impact on the global incidence of HCC[⁵⁹]. Further advances in our understanding of the molecular pathogenesis of HCC hold promise in improving the diagnosis and treatment of this highly lethal cancer[⁴].

Footnotes

P- Reviewers: Chen Z, Vinciguerra M S- Editor: Gou SX L- Editor: A E- Editor: Ma S

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