Is Interferon-Free Treatment for Hepatitis C Just a Dream?

From Medscape Gastroenterology > Ask the Experts

William F. Balistreri, MD

Posted: 08/27/2012

Question

What are our evidence-based treatment strategies for hepatitis C? Will we ever have an interferon-free regimen?

Response from William F. Balistreri, MD
Professor of Medicine, University of Cincinnati College of Medicine; Staff Physician, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

The Current Standard Treatment for HCV Infection

Combination therapy with pegylated interferon and ribavirin has long been the standard of care for patients with chronic hepatitis C (HCV) infection. Although effective in achieving high response rates, this regimen is associated with troublesome side effects.^[1] Therefore, the development and approval of effective protease inhibitors, telaprevir and boceprevir, was hailed as a new era of therapy for patients with hepatitis C genotype 1 infection.^[2,3]

Interferon-Free Treatment: No Longer a Dream?

Several studies were presented at both Digestive Disease Week (DDW) 2012 in May and at the European Association for the Study of the Liver (EASL) annual meeting in April 2012 that documented that these direct-acting antiviral agents allow more effective and shorter durations of treatment. For example, in patients infected with HCV genotype 1 for whom previous standard therapy failed to eliminate the virus, treatment with either of these protease inhibitors was shown to be significantly more effective, with sustained viral response rates 2- to 3-fold higher than with traditional therapy.

An American Association for the Study of Liver Diseases plenary session presentation during DDW 2012 reported that when telaprevir was used in combination with pegylated interferon and ribavirin, the dose of ribavirin could be substantially reduced.^[4] Reduction of the ribavirin dose to less than 600 mg/day had no substantial effect on sustained viral response (SVR) rates in patients who received telaprevir combination treatment. In another study, when boceprevir was used in combination with pegylated interferon and ribavirin, SVR was achieved in patients who had been nonresponsive to previous therapy.^[5]

Despite the optimism about the prospects for this treatment of HCV, the fact that telaprevir and boceprevir must be used in combination with pegylated interferon and ribavirin is a persisting concern. This is far from the ideal regimen. In fact, because of poor tolerability, many treatment candidates will decide not to pursue treatment or to defer treatment until a simpler regimen is available. However, other studies suggest that an interferon-free regimen (and perhaps even a ribavirin-free regimen) is no longer a dream. Various compounds encompassing several distinct drug classes are currently under development. These drugs bring us one step closer to the long sought-after ideal: the ability to remove interferon injections from treatment for HCV.

Targeting Novel Treatment Options

Two studies presented at the EASL annual meeting in April 2012 revealed novel treatment options for HCV genotype 1-infected patients who are unable to take interferon-based therapy. The strategy was based on a 12-week combinations of DAA (direct-acting antiviral) interferon-free therapy.

In the first study, ABT-450, a potent inhibitor of the HCV NS3 protease, was coadministered with ritonavir (ABT-450/r), a CYP3A inhibitor, to maintain high ABT-450 exposures and support once-daily dosing.^[6] ABT-072 is a non-nucleoside inhibitor of HCV NS5B polymerase. The investigators reported that 91% of treatment-naive, noncirrhotic patients infected with HCV genotype 1 (the interleukin-28B CC genotype) achieved SVR after 12 weeks, and 82% achieved SVR at 36 weeks. The combination of ABT-450/r plus ABT-072 plus ribavirin was well tolerated over the 12 weeks of treatment.

In a companion study, ABT-450/r was coadministered with ABT-333, another non-nucleoside inhibitor of HCV NS5B polymerase.^[7] The combination of ABT-450/r plus ABT-333 plus ribavirin without interferon in HCV genotype 1-infected patients was well tolerated during 12 weeks of treatment. Overall, 93%-95% of treatment-naive patients infected with HCV genotype 1 achieved SVR after 12 weeks of treatment. Therefore, ABT-450/r plus ABT-333 plus ribavirin for 12 weeks has the potential to achieve SVR in a high proportion of patients without the use of interferon. Further trials of these agents are under way.

Predicting Response and Nonresponse

In the interim, how can we tailor therapy and predict response rates? Investigators reported that patients infected with HCV genotypes 2 and 3 achieved SVR rates of 70%-80% in clinical trials. However, in real-life settings, lower SVR rates in the range of 55%-65% are reported. In work presented at DDW 2012, predictive factors for nonresponsive patients with genotypes 2 and 3 included daily alcohol intake greater than 40 g, HIV coinfection, low thyroid-stimulating hormone levels, the presence of cirrhosis, and the duration of infection.^[8] These risk factors should be assessed and may suggest the need for an intensified treatment course.

Further data presented at DDW 2012 documented the value of a major genetic predictive factor: a single nucleotide polymorphism in the upstream region of the interleukin-28B gene.^[9] Genotype CC was the strongest factor predictive of SVR in patients with HCV genotype 1 who were treated with pegylated interferon and ribavirin. This CC genotype was also shown to be associated with a significantly higher rate of spontaneous clearance in both white and black patients with exposure to HCV. This information will be of value when counseling patients.

The Bottom Line

The bottom line is that the intense interest in developing and validating new strategies for the treatment of chronic HCV promises to eliminate the need for interferon and perhaps even ribavirin.

Source

Raloxifene Aids HCV Therapy in Some Postmenopausal Women

From Reuters Health Information

By David Douglas

NEW YORK (Reuters Health) Sep 03 - The addition of raloxifene to standard treatment for hepatitis C virus (HCV) infection in postmenopausal women appears to improve outcome in many, according to Japanese researchers.

Dr. Jun Hayashi of Kyushu University Hospital and colleagues note that because pegylated interferon therapy is more effective in younger than older women it suggests a potential link to reduced estrogen secretion. In addition, early menopause has been reported to be the most predictive factor for failure to achieve a sustained viral response (SVR).

Raloxifene is an oral selective estrogen receptor modulator. Such agents have been suggested to function as estrogen agonists that directly protect hepatocytes and control liver fibrosis.

In a paper online August 13 in the Journal of Hepatology, the researchers report that to examine whether this might be of help, they studied 127 postmenopausal women with genotype 1b chronic HCV.

They were randomized to treatment with pegylated interferon alpha 2a and ribavirin with or without raloxifene 60 mg per day. Planned treatment duration was 48 weeks and all patients were followed for 24 weeks after cessation of treatment.

At this point, the SVR rate was significantly higher in the raloxifene group (61.3% vs. 34.4%, p=0.0051).This was also true of end of treatment response (88.7% versus 68.9%, p=0.0132).

Comparison by interleukin-28B genotype showed that response was significantly greater in the raloxifene patients with interleukin-28B TT compared to their counterparts who did not receive the agent (72.5% vs. 39.2%, p=0.0014). This was not true of carriers of the minor IL28B allele.

Summing up, Dr. Hayashi told Reuters Health by email that the raloxifene-mediated improvement in response is limited to patients homozygous for the major allele of IL28B, and studies are needed in other ethnic groups. Yet the agent "may be a promising candidate as an adjuvant in the antiviral treatment of postmenopausal women with chronic hepatitis C."

SOURCE: http://bit.ly/OzkYiQ

J Hepatol 2012.

Source

Does your knowledge about HIV/AIDS hold up?

By Esha Gupta
From KPC Medical College and Hospital, Kolkata
Posted Sep 7th 2012 10:00AM

Does your knowledge about HIV/AIDS hold up? – Part 1

Several inaccurate myths about HIV and AIDS are still widely believed.

Officially reported by the Centers for Disease Control (CDC) in 1981, AIDS has become a global healthcare problem, with cases being identified in over 190 countries. From 1981 until 2006, AIDS has lead to the death of over 25 million people and orphaning 16.6 million children worldwide.

Misunderstandings of the disease have been fueled by fear, denial and ignorance and culminated in these widespread myths that not only placed people at risk, but have caused undue ostracism to many of those living with HIV or AIDS.

1. The full form of HIV is Human Immunodeficiency Virus.
   TRUE. The Human Immunodeficiency Virus is a retrovirus that attacks the immune cells of the body. When it infects a person, HIV attacks cells of the immune system leading to a decreased immune response. However, the effects of the disease may not be seen for many years.
2. The full form of AIDS is Acquired Immunodeficiency Syndrome.
   TRUE. The Acquired Immunodeficiency Syndrome occurs when the immune cells of the body have been reduced to a critical level. The ravaged immune system is no longer able to cope with the various stresses on the body. When this occurs, a person with AIDS becomes susceptible to a number of diseases which would not normally harm a healthy person..
3. HIV/AIDS can spread by touching, hugging, kissing, sharing meals or even sharing the same utensils.
   FALSE. Numerous studies have shown that HIV cannot be spread by casual contact with a individual afflicted with the disease. The virus may be transmitted through exposure to seminal fluids, blood and breast milk between individuals, but is not transferred in saliva. These fluids can come from, or enter through genital, oral and anal routes as well as open wounds and needle injections.
4. HIV/AIDS spreads by the use of common needles (intravenous drug abuse).
   TRUE. Drug abuse is one of the leading causes of the spread of HIV among all population groups around the world. The practice of sharing needles among drug abusers has lead to rampant spread in many parts of the world, including India. Some governments have proposed programs to provide clean, sterile needles to prevent transmission among those using injected drugs.
5. Oral contraceptive pills (OCPs), spermicides, diaphragms, and sponges prevent HIV infection.
   FALSE. While the use of oral contraceptive pills, spermicides, diaphragms and sponges provide protection against pregnancy, they offer little protection against infection by HIV. Studies have shown even diaphragms to be ineffective at preventing HIV as they cannot cover the all of the lining of the vagina through which the virus may enter. Currently the best method of prevention is abstinence or proper use of a male condom during intercourse.

Does your knowledge about HIV/AIDS hold up? – part 2

1. The proper use of condoms during intercourse prevents the spread of HIV infections.
   TRUE. Numerous studies have shown that the proper use of the male condom significantly lowers the risk of transmission of HIV between sexual partners. In addition, the female condom has shown promising effectiveness in preventing HIV transmission.
2. HIV/AIDS is a curable disease.
   FALSE. Currently there is no effective cure for HIV or AIDS. However, there are many drugs available that are shown to help slow the progress of the disease and dramatically increase quality of life and life expectancy for those living with the disease. Continued research on new medicines and other medical techniques show promise for the treatment of those infected, but the best cure is prevention by taking the proper precautions.
3. A person can spread HIV/AIDS, even if being treated for it.
   TRUE. Even if a person is being treated for HIV or AIDS, it is still possible to spread the disease to their partner. Most treatments aim at preventing the virus from copying itself within the body, but are unable to remove it once it is present. The viral particles permeate into many of the body excretions and still pose a risk. It is still important to observe safe sex practices even while being treated.
4. HIV can be transmitted by mosquito bite.
   FALSE. There is no evidence to suggest that HIV can be spread through mosquito bites. A mosquito may feed on the blood of an infected individual, however that blood remains within the stomach of the mosquito and does not come into contact with any subsequent person that the mosquito feeds on.
   If a mosquito is killed against the skin, it may expose a person to the virus as the blood within the mosquito's stomach can be smeared into an open wound. However, the possibility of transmittance in this way is very remote.
5. You can tell if a person is HIV positive, just by the way they look.
   FALSE. It is a common misconception that a person infected with HIV will appear to be sick. This belief is often used as an excuse not to practice safe sex. However, the affects of HIV may remain unapparent for several years to even a decade. The appearance of open wounds which many people are familiar with are usually only seen in late stage infection by HIV, at the onset of AIDS.

Part 1 Source

Part 2 Source

Analysis: Use of pill to prevent HIV may be limited in U.S

September 07, 2012|Deena Beasley | Reuters

LOS ANGELES (Reuters) - The first preventive pill for HIV has been hailed as a landmark in the fight against AIDS in the United States, but experts say only a small percentage of those at risk will benefit from it.

U.S. health regulators last month approved Gilead Sciences Inc's Truvada -- already used globally to treat the human immunodeficiency virus -- for preventing the infection in healthy people at high risk of contracting the virus that causes AIDS.

A number of factors will limit the drug's use for preventing HIV, including the fact that in the United States many people most at risk of infection, as well as their sexual partners, do not have consistent access to healthcare. Even for those with coverage, insurance reimbursement for a $14,000-a-year drug is expected to be tricky.

In addition, therapy with the drug would require otherwise healthy young people to take a pill each day, plus show up for HIV testing every three months.

"There are a number of rather significant implementation challenges," said Dr. Stephen Morin, director of the Center for AIDS Prevention Studies at the University of California at San Francisco. "Part of it has to do with the requirement to take a pill a day, which could be addressed by a more long-term administration of the drug."

Scientists are exploring a variety of tactics for using AIDS drug formulations to prevent HIV infection, including long-acting injections, gels and vaginal rings.

About 50,000 new HIV infections are reported each year in the United States. The number of patients taking Truvada to prevent HIV will likely be "a lot less" than that, said Howard Jaffe, head of the Gilead Foundation and a member of the company's senior management since 1991.

Gilead declined to give its own sales estimate.

"We are not expecting a meaningful increase or uptick in Truvada use from it," Jaffe said, referring to the FDA prevention approval. "We do expect it to enter into the conversation with regard to certain high-risk populations."

He said use of Truvada to prevent HIV infection will likely be most important outside of the United States, as developing countries where AIDS remains an epidemic look for additional ways to curb transmission of the virus.

Gilead has deals, mainly with generic drugmakers in India, to produce low-cost versions of its drugs for use in sub-Saharan Africa and other developing regions.

Dr. Paul Volberding, director of the Center for AIDS Research at the University of California at San Francisco, says Truvada could become a valuable tool for "a small fraction of people" who understand they have a high risk of exposure -- mainly female sex workers whose clients won't use condoms and gay men who decide they are going to engage in riskier sex.

"There is an easy consensus now that somebody that is on treatment and fully suppressed has either zero, or close to it, risk of transmitting the virus," Volberding said.

He and others emphasized that wider testing for HIV -- and treatment of already infected patients -- are the keys to reducing HIV incidence.

Of the 1.2 million Americans estimated to be infected with human immunodeficiency virus, almost 20 percent of them do not know it, according to the U.S. Centers for Disease Control and Prevention .

A recent study by the CDC found that 41 percent of U.S. HIV patients are under continual care of a doctor and just 28 percent had the viral infection under control.

PREVENTION THROUGH PREP

The U.S. Food and Drug Administration in July approved Truvada for adults who do not have the virus but may engage in sexual activity with HIV-infected partners, a concept known as pre-exposure prophylaxis (PrEP). The approval was for use in combination with safer sex practices, such as condoms.

The drug, which combines two anti-HIV drugs in one pill, was already approved for use with other antiretroviral agents to treat patients 12 and older who are infected with the virus. Antiretrovirals are designed to block various steps in replication of the virus.

Critics, including the AIDS Healthcare Foundation, a non-profit provider of HIV/AIDS medical care, argue that Truvada was shown to be only partially effective in preventing HIV transmission, can cause side effects including kidney problems and may cause healthy people to become resistant to it.

No U.S. public money has been allocated for treating uninsured individuals who do not already have AIDS, and some doctors question the degree to which insured patients would be covered.

"I would find it very difficult for there to be a provision to support funding for such a program when we have (HIV-positive) patients on waiting lists," said Murray Penner, deputy executive director at the National Alliance of State and Territorial AIDS Directors, which represents public-health departments.

Source

Vaccine efficacy increased against certain HIV viruses

Scientists used genetic sequencing to discover new evidence that the first vaccine shown to prevent HIV infection in people also affected the viruses in those who did become infected. Viruses with two genetic “footprints” were associated with greater vaccine efficacy. The results were published today in the online edition of the journal Nature.

“This is the first time that we have seen pressure on the virus at the genetic level due to an effective HIV vaccine,” said Morgane Rolland, Ph.D., a scientist at the U.S. Military HIV Research Program and lead author of the study. The analysis revealed evidence of a vaccine-induced immune response on two sites of Env-V2 region located on HIV’s outer coat. For viruses carrying these two particular signatures, the vaccine efficacy increased to 80 percent.

“These findings reinforce both the RV144 result and the previous study showing that antibodies directed at the V1V2 region reduce the risk of infection. Taken together the work suggests that the Env-V2 region could be a critical target for future HIV vaccines,” noted Col. Jerome Kim, senior author on the study.

“Genetic sequencing is an important and independent assessment of the immune responses induced by the vaccine,” said Paul Edlefsen, Ph.D., a biostatistitian at the Statistical Center for HIV/AIDS Research and Prevention (SCHARP) who co-led the study. Researchers examined HIV genome sequences from 110 volunteers who participated in the Thai HIV vaccine trial, RV144, and who subsequently became infected with HIV. Results indicate that the HIV viruses infecting trial participants were different in persons who received vaccine compared to those who received placebo.

Researchers focused their analysis on the V2 portion of the HIV virus after a study published earlier in 2012 found that antibodies specific to the V1V2 region of the HIV genome correlated with lower risk of infection. This new genetic sequencing study showed that the viruses that broke through or escaped from these immune responses have genetic differences in the same V2 region, indicating that the vaccine exerted pressure in this region.

HIV viruses that escape from antibodies and manage to infect a person have genetic footprints, or mutations, that can prevent them from being recognized by the immune system. These changes can be seen in the genetic sequence of the virus. The research team sequenced more than a thousand full-length viruses to look very carefully at which changes corresponded to “escape” mutations.

“This study underscores the realistic optimism you see in the HIV vaccine research field today. We are making substantive progress in understanding what it will take to develop a more effective HIV vaccine which will ultimately help us end this pandemic.” said Col. Nelson Michael, director of MHRP.

The study team included researchers with the U.S. Army’s Military HIV Research Program (MHRP) at the Walter Reed Army Institute of Research, The Statistical Center for HIV/AIDS Research and Prevention (SCHARP) at the Fred Hutchinson Cancer Research Center and the University of Washington. The project was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DoD).

Source

CDC: Baby boomers be tested for Hepatitis C

Published Sep 10, 2012 at 11:30 am (Updated Sep 10, 2012)

By Ronald Valdiserri, M.D., M.P.H.

WASHINGTON, D.C. — All Americans born from 1945 through 1965 should get a one-time test for hepatitis C, the Centers for Disease Control and Prevention (CDC) recommended last month.
More than 2 million U.S. baby boomers are infected with hepatitis C — and most of them don’t know it. They account for more than 75 percent of all American adults living with the virus. More than 15,000 Americans, most of them baby boomers, die each year from hepatitis C-related illness, such as cirrhosis and liver cancer, and deaths have been increasing steadily for over a decade and are projected to grow significantly in coming years.

CDC cites studies showing that many baby boomers were infected with the virus decades ago, do not perceive themselves to be at risk, and have never been screened.

The new recommendations are aimed at identifying more hidden infections among those most affected by the disease and reducing the rising toll of hepatitis C-related illness and death in the United States. The new recommendations expand CDC’s risk-based recommendations, which called for testing only people with certain known risk factors for hepatitis C infection.

Risk-based screening will continue to be important, but that approach alone is not sufficient.
CDC estimates one-time hepatitis C testing of baby boomers could identify more than 800,000 additional people with hepatitis C. And with newly available therapies that can cure up to 75 percent of infections, expanded testing — along with linkage to appropriate care and treatment — would prevent the costly consequences of liver cancer and other chronic liver diseases and save more than 120,000 lives.

“A one-time blood test for hepatitis C should be on every baby boomer’s medical checklist,” said CDC Director Thomas R. Frieden, M.D., M.P.H. “The new recommendations can protect the health of an entire generation of Americans and save thousands of lives.”

The expanded recommendations have been finalized after a public comment period and were published in the Aug. 17 issue of CDC’s Morbidity and Mortality Weekly Report.

CDC has also updated its online Hepatitis Risk Assessment to include the new age cohort recommendation. This confidential tool — at www.cdc.gov/hepatitis/riskassessment — allows individuals to determine their risk for viral hepatitis by answering questions privately, either in their home or a health care setting. They can then print tailored recommendations based on CDC’s testing and vaccination guidelines for viral hepatitis to discuss with their doctor.

Ronald Valdiserri is Deputy Assistant Secretary for Health, Infectious Diseases, and director of the Office of HIV/AIDS and Infectious Disease Policy, U.S. Department of Health and Human Services.

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Survival 'Excellent' Following Living Donor Liver Transplantation for Acute Liver Failure

ScienceDaily (Sep. 6, 2012) — Patients in Japan who underwent living donor liver transplantation (LDLT) for acute liver failure (ALF) were classified as having excellent outcomes, with ten-year survival at 73%. The findings, published in the September issue of Liver Transplantation, a journal of the American Association for the Study of Liver Diseases (AASLD), suggest that the type of liver disease or treatment plan does not affect long-term patient survival following LDLT. Donor and patient age, however, does impact long-term outcome post-transplant.

According to the AASLD, roughly 2,000 Americans develop ALF -- formally called fulminant hepatitis -- each year, with many of these cases caused by acetaminophen (Tylenol) overdose, drug-induced liver injury, autoimmune liver disease, or viral hepatitis. Previous studies report patient survival from ALF was less than 15% before the era of liver transplantation and significantly better at more than 65% following transplantation.

LDLT -- when a portion of a healthy liver from a living donor is used for transplantation -- was developed as an alternative treatment option to overcome the shortage of deceased donor organs. A 2007 study by de Villa et al. found that LDLT accounts for less than 5% of liver transplants in the U.S. and Europe compared to more than 90% in Asia excluding mainland China.

"ALF is a rare, life-threatening condition where the rapid deterioration of liver function causes changes in mental activity and disrupts the body's blood clotting capabilities," explains lead author Dr. Yasuhiko Sugawara, Associate Professor in the Graduate School of Medicine at the University of Tokyo in Japan. "Expanding knowledge of treatment options, such as LDLT, that improve patient outcome is imperative."

Using data from the Intractable Liver Disease Study Group of Japan, researchers identified 209 ALF candidates who underwent living donor liver transplantation. The authors report that in patients who underwent LDLT the cumulative one-year, five-year and ten-year survival rates following transplantation were 79%, 74%, 73%, respectively. Patient age impacted short-term and long-term mortality, while donor age only affected long-term patient mortality.

"Our study demonstrates the benefit of LDLT in a Japanese population, which has less access to deceased donor organs," concludes Dr. Sugawara. "Prospective studies are needed to determine the overall impact of LDLT in all patients with ALF."

In a related editorial also published in Liver Transplantation, Professor Chung-Mau Lo with the University of Hong Kong and Queen Mary Hospital in Hong Kong, China, notes that LDLT for ALF patients has generated debate among experts in several areas: (1) reports in Western countries of inferior outcome with LDLT in high-urgency situations; (2) likelihood of ALF patients receiving a liver in countries with developed deceased organ donation programs; and (3) concern with coercion of donors and a possible increase of donor risk when the evaluation process is rushed in such an urgent situation.

"Deceased donor liver transplantation is dictated by the availability of the organ, and high-risk marginal grafts are frequently used. LDLT allows for early transplant to avoid waitlist mortality and better timing of the operation, which can be performed at the first sign of patient deterioration," concludes Professor Lo. "LDLT for ALF has developed in Asia because there is no choice. Is it possible that it may in fact be a better choice?"

Story Source:

The above story is reprinted from materials provided by Wiley, via AlphaGalileo.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal References:

1. Noriyo Yamashiki, Yasuhiko Sugawara, Sumihito Tamura, Nobuaki Nakayama, Makoto Oketani, Koji Umeshita, Shinji Uemoto, Satoshi Mochida, Hirohito Tsubouchi, Norihiro Kokudo. Outcomes after living donor liver transplantation for acute liver failure in Japan: Results of a nationwide survey. Liver Transplantation, 2012; 18 (9): 1069 DOI: 10.1002/lt.23469
2. Chung-Mau Lo. Living donor liver transplantation for acute liver failure: No other choice. Liver Transplantation, 2012; 18 (9): 1005 DOI: 10.1002/lt.23492

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Antibody Prevents Hepatitis C Infection in Animal Model

ScienceDaily (Aug. 30, 2012) — A monoclonal antibody therapy developed by MassBiologics of the University of Massachusetts Medical School (UMMS) and tested in an animal model at the Texas Biomedical Research Institute, prevents infection by the hepatitis C virus (HCV).

Researchers found that the human monoclonal antibody targeting the virus protected chimpanzees from HCV infection in a dose-dependent manner in a study conducted at Texas Biomed's Southwest National Primate Research Center in San Antonio. Chimpanzees are the only species other than humans that can be infected by the hepatitis C virus and therefore the results from this study were critical in the development of the monoclonal antibody. The new report by scientists from MassBiologics; Texas Biomed; the National Institutes of Health (NIH); and Merck Research Laboratories, and funded by MassBiologics and NIH, appears in the August 30th issue of PLoS Pathogens. Researchers had previously demonstrated that the monoclonal antibody, called HCV1, blocks HCV from infecting liver cells in laboratory tissue culture.

"This is an important proof-of-concept study demonstrating a high dose of neutralizing antibody can protect the liver from HCV infection using monoclonal antibodies in a study that was designed to mimic the transplantation setting," said study co-author Robert E. Lanford, Ph.D., of Texas Biomed.

"One can envision improving on these results with a cocktail of antibodies or by using this antibody with some of the newer antivirals currently in clinical trials. Infection of the new donor liver by residual virus in the patient is one of the major obstacles preventing a full recovery in these patients," Lanford added.

MassBiologics has been pursuing the development of HCV1 as a therapy for patients with end-stage liver disease undergoing liver transplantation as a result of HCV infection. HCV1 is a monoclonal antibody that binds to the surface of the HCV virus and blocks the ability of the virus to enter liver cells.

HCV damages the liver and is the leading indication for liver transplantation, diagnosed in about half of the 6,000 patients who receive liver transplants each year in the United States. According to the US Centers for Disease Control and Prevention (CDC), 3.2 million Americans are chronically infected with HCV and approximately 10,000 die annually of the disease. Globally, as many as 170 million people are estimated to suffer from HCV infection. The CDC recently recommended that everyone born from 1945 to 1965 should be screened for HCV regardless of whether they have known risk factors.

For patients with end-stage liver disease from HCV infection, liver transplantation is the only option. While it can be a life-saving treatment, transplantation does not cure the disease. In nearly all cases, the patient's new liver is eventually infected by HCV because the virus remains in the patient's bloodstream during surgery. The course of recurrent HCV disease is accelerated after transplantation and up to 20 percent of transplant patients develop cirrhosis within five years. Unfortunately, the standard antiviral drugs currently used to treat HCV prior to the onset of end-stage liver disease are poorly tolerated after liver transplantation, leaving these patients with few options.

This research was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at NIH. The chimpanzee studies performed at the Southwest National Primate Research Center were supported by the NIH primate center grant P51 RR13986 and the NIH facilities grants C06 RR 12087 and C06 RR016228.

Story Source:

The above story is reprinted from materials provided by Texas Biomedical Research Institute.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Trevor J. Morin, Teresa J. Broering, Brett A. Leav, Barbra M. Blair, Kirk J. Rowley, Elisabeth N. Boucher, Yang Wang, Peter S. Cheslock, Michael Knauber, David B. Olsen, Steve W. Ludmerer, Gyongyi Szabo, Robert W. Finberg, Robert H. Purcell, Robert E. Lanford, Donna M. Ambrosino, Deborah C. Molrine, Gregory J. Babcock. Human Monoclonal Antibody HCV1 Effectively Prevents and Treats HCV Infection in Chimpanzees. PLoS Pathogens, 2012; 8 (8): e1002895 DOI: 10.1371/journal.ppat.1002895

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New treatments mean ‘higher success rates’

September 7, 2012 By Pat Kelly

New medications for hepatitis C have been judged cost-effective by the National Centre for Pharmacoeconomics and State reimbursement has been given to the treatments, hailed as a significant breakthrough, reports Gary Culliton.

Chronic hepatitis C poses a public health burden and up to 50,000 Irish people currently have the virus. It is an infectious disease but patients are often asymptomatic for long periods. If it remains untreated, it can lead to severe liver conditions. About 25 per cent of people infected can progress to cirrhosis, which in turn can lead to liver transplantation and liver cancer.

The standard treatment for hepatitis C (peginterferon alfa and ribavirin) is successful in only about 50 per cent of patients with genotype 1, leaving the other 50 per cent without a successful treatment outcome.

For 15 years, hepatitis C treatment barely changed. Last month’s reimbursement approval for new therapy radically changed the treatment environment and heralds a new generation of drugs to treat hepatitis C, according to a leading Dublin hepatologist. “This is a paradigm shift for treatment of the most common type of hepatitis C, genotype 1,” said Dr Raphael Merriman, Consultant Hepatologist at St Vincent’s University Hospital, Dublin. “It is the most important approval of new agents since 1998.

The addition of a protease inhibitor nearly doubles the chances of cure for patients who have never been treated previously and also substantially improves response rates for those who have undergone unsuccessful treatment in the past. Two protease inhibitors — boceprevir and telaprevir — will now be available for Irish patients.”

Drug pipeline

The latest direct-acting antivirals (DAAs) are the first of a whole host of new drugs that will be coming on-stream in the next three-five years. There are between 20 and 30 such drugs in various phases of clinical trials, which will further increase the efficacy of treatment for hepatitis C — hopefully with shorter treatment durations. Some studies even involve the absence of interferon, which is much disliked by patients due to its side-effects.

The protease inhibitors effectively double the ‘cure rate’ among treatment naïve patients: getting rid of the virus, six months after the end of treatment. These are people who have not previously been treated with interferon. The chance of a cure in this group rises dramatically from 40 per cent to between 70 and 75 per cent.

There is greater complexity of care: patients need to be seen and monitored more frequently. However, about two-thirds who are treatment naïve will qualify for shortened treatment. The response rates for people who are treatment experienced are less but still much better than they were, when just interferon and ribavirin were available.

Where there have been prior attempts at treatment, most of those people will require the full 48 weeks of treatment (including a protease inhibitor).

Dr Orla Crosbie, Consultant Hepatologist and Gastroenterologist from CUH, said: “The availability of direct-acting antivirals in Ireland means success rates for treatment will now be significantly higher. In addition, treatment duration will be far shorter for many groups of patients.”

Older drugs were more ‘blunderbuss’ in their effects, Dr Merriman added. A combination of two medications in pill form is currently required, along with the continued use of a subcutaneous injection, and the current standard of treatment is 48 weeks. The new three-drug combination treatment is more efficacious and treatment can now be shortened from 48 weeks to between 24 and 28 weeks, in a majority of those who have not been treated before, he said.

Interferon and ribavirin were much blunter instruments, Dr Merriman explained. The newer agents, such as telaprevir, are much more focused and specific in the target sites where they act, he added.

Thought will be required on the part of hepatologists as to which patients are best suited to which of the new drugs. The consensus is that people with more advanced disease — typically defined as more significant fibrosis or scarring in the liver — should be first in line for treatment.

Protease inhibitors such as boceprevir and telaprevir help stop genotype 1 infection — the strain affecting over 50 per cent of the Irish hepatitis C population. Genotype 1 is the infection least amenable to currently available therapy. Treatment will be rolled out in tandem with the national hepatitis c Register, to analyse data and determine outcomes. Treatment will take place in a limited number of centres (five in Dublin and also at University College Hospital Galway, St Luke’s in Kilkenny and Cork University Hospital) where there is expertise in treating the condition. The new drugs are not aimed at people with hepatitis genotypes 2 and 3.

Once the virus is gone, treatment continues. After 24 weeks following the end of treatment, tests are conducted for the presence of the virus. The relapse rate is very low, said Dr Merriman. If the virus is still gone at this point (Sustained Virological Response, SVR), this effectively translates to a cure. Both in people who have never been treated and those who have been treated before, the SVR rates are nearly double what could be achieved with previous therapy.

The National Centre for Pharmacoeconomics has judged the new protease inhibitors to be cost-effective. Five sentinel studies published in the New England Journal of Medicine (NEJM) last year provided compelling data that these drugs work, explained Dr Merriman. Authorisation for telaprevir is based on results from three phase III clinical trials, ADVANCE, REALIZE and ILLUMINATE. These evaluated the efficacy and safety of telaprevir in combination with peginterferon alfa and ribavirin in more than 2,290 treatment-naïve and previously-treated chronic genotype 1 hepatitis C patients. Data from ADVANCE and REALIZE were published in the June 23 edition of the NEJM. Data from the ILLUMINATE study were published in the September 15 edition.

Because there are three different drugs, the new ‘triple therapy’ (of protease inhibitors, interferon and ribavirin), works on several different mechanisms. One of the new protease inhibitors is given in combination with the previous two-drug combination. Effectively, the treatment suppresses and ultimately eradicates the virus.

Source

Hepatitis C High Viral Load Patients May Benefit From Telaprevir

Posted in: Medical News by Elvis Augustin on September 8th, 2012

Researchers found that telaprevir in combination with peginterferon and ribavirin help patients with hepatitis C. Telaprevir is a virostatic drug that inhibits viral replication.

Hepatitis C can lead to liver failure and even hepatocellular cancer. C virus infection can be transmitted through blood transfusions, sexual intercourse, needle pricks, organ transplants, body piercing, etc.. In the first phase C virus infection is asymptomatic, but gradually nonspecific symptoms such as fatigue occur. There are cases in which C virus infection is manifested by acute symptoms such as nausea, joint pain, muscle pain, etc.. Sometimes jaundice occurs. Some of those infected with the virus C eliminate the infection, some are healthy carriers and some become chronic carriers. Of the latter, about 30% develop cirrhosis and hepatocellular cancer. Cirrhosis brings some complications such as portal hypertension and esophageal varices. The main risk is rupture of esophageal varices with the appearance of upper gastrointestinal bleeding . In addition to this complication, which can be fatal sometimes, there are also other consequences such as bruising, bleeding, endocrine disorders, portal encephalopathy etc. The only way to prevent virus C infection is to increase hygiene measures and halt the transmission because there is no vaccine against C available yet.

Studies by researchers at the Institute for Quality and Efficiency in Health Care (IQWiG) wanted to show what is the effectiveness of telaprevir when treatming viral hepatitis C. They compared the effects of several groups of patients treated with standard therapy (peginterferon and ribavirin) or with triple therapy, ie peginterferon, ribavirin and telaprevir. The results were different depending on the group of patients and depending on outcome (mortality, morbidity, etc.). Telaprevir efficacy studies were performed on several groups of patients. The studies were conducted in patients with high viral load, patients who already had cirrhosis or not. The findings were different for different groups of patients. For example, it was found that telaprevir has an added benefit to the patients with high viral load, but without cirrhosis. Also, the researchers also found that telaprevir bring added benefice in patients without cirrhosis and in non-responders cirrhosis patients.

However, in patients without cirrhosis it was found that telaprevir has no benefit and can even cause some side effects, such as rash and anemia. It should be noted however that these adverse effects were considered as not serious and were not a restriction for patients with high viral load. In addition, for patients without cirrhosis and low viral load, triple therapy had no benefit compared with standard therapy (peginterferon and ribavirin).

Source

Eight Common Misconceptions About HIV Vaccines That May Impede Progress in Controlling the AIDS Epidemic

From Future Virology

Peter A Newman

Posted: 09/07/2012; Future Virology. 2012;7(8):737-740. © 2012 Future Medicine Ltd.

Abstract and Introduction

Abstract

"The acceptability of future HIV vaccines is not guaranteed; in fact, achieving broad uptake becomes even more consequential in the case of partially efficacious vaccines, which are less acceptable to end users."

Introduction

The discovery of a safe and efficacious HIV vaccine would be among the most significant contributions to global health in the early 21st century. Despite current prevention methods and groundbreaking advances in antiretroviral treatment, an estimated 2.5 million people worldwide are infected with HIV every year.^[101] In the USA, annual HIV incident infections (estimated 55,000) have not abated for two decades.^[1] In low- and middle-income countries, new infections continue to outpace access to treatment,^[101] and many persons at risk lack access to existing prevention technologies.^[2]

New and emerging HIV prevention technologies, including antiretroviral-based oral pre-exposure prophylaxis and topical microbicides, may yield substantial contributions to controlling the epidemic. Nevertheless, fundamental sociobehavioral and structural challenges, which continue to dilute the effectiveness of existing prevention technologies requiring daily or pericoital usage, suggest that a vaccine is needed to reverse HIV on a population level.

The purpose of identifying HIV vaccine misconceptions is neither to discredit vaccine research nor to devalue the tremendous global importance of a HIV vaccine. Rather, identification of gaps in our conceptions and practices may reveal opportunities to promote the success of the HIV vaccine endeavor.

Misconception 1: Efficacy in Clinical Trials Will Translate to Effectiveness in the Real World

HIV vaccine development faces tremendous scientific challenges. Indeed, as the argument goes, without addressing these we may not have the luxury of dealing with the mundane challenges of implementation. However, to identify clinical trial efficacy as the end game allows predictable and formidable, yet surmountable challenges to hamper or even undermine the success of a vaccine in controlling the epidemic.

A quick overview of vaccines that are currently available, particularly adult vaccines for diseases that can be sexually or parenterally transmitted, supports the importance of an implementation science approach.^[3] Coverage for highly efficacious hepatitis B vaccines, licensed for over 20 years, is estimated at 10–30% among people who inject drugs in New York City, NY, USA,^[4] with wide variability (3–70%) reported among men who have sex with men in the USA^[5] – groups at high risk for HIV infection.^[1] HPV vaccine coverage remains suboptimal among US women (48.7%) and men (1.4%) aged 13–17 years, amidst ongoing concerns about safety, efficacy, behavioral disinhibition and cost–effectiveness.^[6] Vaccine efficacy does not ensure effectiveness. An implementation science approach directs us to fund and advance rigorous scientific inquiry – before a product is publicly available – to address ubiquitous gaps between product efficacy in clinical trials and effectiveness in the real world.^[3]

Misconception 2: Once a Licensed HIV Vaccine is Made Accessible, People Will Line Up to be Vaccinated

Although it is vital to address organizational and structural challenges for future HIV vaccine dissemination and implementation at legal, economic, political and institutional levels, vaccine acceptability among end users remains an indelible part of the equation.^[7] A systematic review of 20 studies (n = 7576) identified HIV vaccine acceptability among potential end users ranging from 37 to 94 on a 100-point scale, with significantly lower acceptance of a moderate (50%) efficacy (40.4/100) versus a high (80–95%) efficacy vaccine (73.8/100).^[7] Concerns about vaccine efficacy and safety, perceptions of HIV risk and vaccine fears were significantly associated with acceptability. The acceptability of future HIV vaccines is not guaranteed; in fact, achieving broad uptake becomes even more consequential in the case of partially efficacious vaccines, which are less acceptable to end users.

Misconception 3: We Should Not Disclose Too Much Information About HIV Vaccine Development & Clinical Trials as the General Public Cannot Handle It

Although this view is certainly not unanimous, concerns that providing piecemeal information to the general public will result in the fueling of misconceptions and false hopes may support the withholding of information. However, in the absence of active communication and ongoing engagement with information from bona fide scientific and public health sources, the knowledge vacuum is more likely to be filled with sensationalistic media stories, conspiracy theories and mistrust.^[8,9] In addition to counteracting myths and misconceptions that portend danger and malevolence on the part of medical researchers and the government, it is important to temper unrealistic hopes for HIV vaccine effectiveness. Magical expectations may promote an 'early idealization, sudden condemnation' phenomenon, which contributed to delicensure of a previously released rotavirus vaccine.^[9] In the case of a partially efficacious HIV vaccine, initial breakthrough infections may not only call into question the value of vaccination; they might be wrongfully attributed to the vaccine itself, which could pose substantial obstacles to uptake.^[10]

Misconception 4: A HIV Vaccine Will Obviate the Complex Sociobehavioral Challenges That Arise in Preventing an Infectious Disease Largely Spread by Sex & Injecting Drug Use, Which Disproportionately Affects Poor & Marginalized Populations & the Developing World

HIV vaccines would mitigate many of the thorny real-world challenges that pose obstacles to the effectiveness of condoms and are likely to dilute the effectiveness of pre-exposure prophylaxis regimens requiring daily usage. Yet, there is no vaccine to inoculate against sociostructural obstacles that arise due to poverty, lack of access to healthcare, healthcare discrimination, HIV stigma, and discrimination against women and sexual minorities. The development of evidence-informed interventions to address what are likely to be pervasive obstacles to HIV vaccine coverage may not only enhance vaccine effectiveness, but may increase the effectiveness of existing HIV prevention regimens, both behavioral and biomedical.

Misconception 5: HIV Vaccine Trials are a Biomedical Endeavor

Despite premature biomedical HIV prevention trial shutdowns in low- and middle-income countries that might have been averted with: more extensive community engagement and preparedness;^[11,12] inconsistent adherence to product usage that has posed serious threats to efficacy in clinical trials and interpretation of trial results;^[13] potential harms due to risk behavior increases among trial volunteers as a result of preventive misconception;^[14] and documented social impacts of trial participation,^[15] HIV vaccine trial teams are characterized by minimal (if any) inclusion of social scientists. Meaningful integration of social scientists on HIV vaccine trial teams across the trajectory of clinical trials, from community preparedness and protocol development through post-trial dissemination of information, is vital to address the sociobehavioral challenges of clinical trial implementation. Beyond supporting the safe, ethical and successful conduct of clinical trials, funding and integration of social science research in the context of HIV vaccine trials may also promote evidence to support future dissemination of post-licensure HIV vaccines.

Misconception 6: Given High Rates of New Infections Among Many Populations, a Sufficient Number of Volunteers Will Enroll in HIV Vaccine Clinical Trials for the Foreseeable Future

Despite the best of intentions, it is the nature of clinical trials that they often do not result in efficacious products; sometimes they result in unexpected harms.^[16] Studies of trial participants,^[17,18] most-at-risk populations^[19] and civil society representatives^[20] conducted in the wake of HIV vaccine trials that were terminated early reveal mixed reactions. Some participants reported sustained trust in trial investigators and HIV vaccine research, and strong willingness to participate in future research; others retroactively doubted the integrity of the informed consent process, felt betrayed and indicated they would not participate in future trials. The evidence suggests that continued willingness to participate cannot be taken for granted. Greater attention to maintaining transparency in the informed consent process, positive personal relationships with trial staff, and open and ongoing two-way communication between investigators and participants during and after trials are key elements of sustaining positive relationships with potential volunteers and communities.^[17–20]

Misconception 7: Introduction of a HIV Vaccine Will Result in Risk Compensation

Sociobehavioral^[21] and mathematical modeling^[22] studies indicate the possible impact of increased post-vaccination risk behaviors in response to the belief that one is protected against HIV infection. Risk compensation is indeed an important phenomenon that could theoretically result in a worsened post-vaccine epidemic scenario. But it is far from a fait accompli. Rigorous investigations of risk compensation in the context of existing and future biomedical prevention technologies is precisely important to support evidence-informed interventions to mitigate this modifiable risk.^[23]

Misconception 8: HIV Vaccine Misconceptions are the Unique Provenance of Nonscientists

An overview of several important, some pervasive, misconceptions toward HIV vaccines, as evidenced in our current practices of funding research, implementing trials and often, hoping for the best, highlights what may be another common misconception: that the most consequential HIV vaccine misconceptions originate from the general public. However, misconceptions among biomedical and clinical researchers, clinicians, policymakers, public health and social service professionals and research funders may enable what might otherwise be modifiable barriers to negatively impact on HIV vaccine trials and the future effectiveness of vaccines in controlling the epidemic.

To the extent we address common misconceptions that constrain scientists and researchers in advancing HIV vaccines, we can thereby unleash the full potential of social and biomedical science to serve the global HIV vaccine endeavor. We may also achieve welcome collateral benefits by helping to counter HIV vaccine misconceptions that might be more easily attributed solely to lack of scientific literacy on the part of the general public.

References

1. Hall HI, Song R, Rhodes P et al. Estimation of HIV incidence in the United States. JAMA300,520–529 (2008).
2. Gayle HD. Curbing the global AIDS epidemic. N. Engl. J. Med.348,1802–1805 (2003).
3. Woolf SH. The meaning of translational research and why it matters. JAMA299(2),211–213 (2008).
4. Amesty S, Ompad DC, Galea S et al. Prevalence and correlates of previous hepatitis B vaccination and infection among young drug-users in New York City. J. Community Health33(3),139–148 (2008).
5. Matthews JE, Stephenson R, Sullivan PS. Factors associated with self-reported HBV vaccination among HIV-negative MSM participating in an online sexual health survey: a cross-sectional study. PLoS One7(2),E30609 (2012).
6. Stupiansky NW, Alexander AB, Zimet GD. Human papillomavirus vaccine and men: what are the obstacles and challenges? Curr. Opin. Infect. Dis.25(1),86–91 (2012).
7. Newman PA, Logie C. HIV vaccine acceptability: a systematic review and meta-analysis. AIDS24(11),1749–1756 (2010).
8. Roberts KJ, Newman PA, Duan N, Rudy ET. HIV vaccine knowledge and beliefs among communities at elevated risk: conspiracies, questions and confusion. J. Natl Med. Assoc.97(12),1662–1671 (2005).
9. Danovaro-Holliday MC, Wood AL, LeBaron CW. Rotavirus vaccine and the news media, 1987–2001. JAMA287(11),1455–1462 (2002).
10. Newman PA, Seiden D, Roberts K, Duan N. A small dose of HIV? HIV vaccine mental models and risk communication. Health Educ. Behav.36(2),321–333 (2009).
11. Singh JA, Mills EJ. The abandoned trials of pre-exposure prophylaxis for HIV: what went wrong? PLoS Med.2(9),E234 (2005).
12. Newman PA. Towards a science of community engagement. Lancet367(9507),302 (2006).
13. van der Straten A, van Damme L, Haberer JE, Bangsberg DR. Unraveling the divergent results of PrEP trials for HIV prevention. AIDS26(7),F13–F19 (2012).
14. Simon AE, Wu AW, Lavori PW, Sugarman J. Preventive misconception: its nature, presence, and ethical implications for research. Am. J. Prev. Med.32(5),370–374 (2007).
15. Allen M, Lau CY. Social impact of preventive HIV vaccine clinical trial participation: a model of prevention, assessment and intervention. Soc. Sci. Med.66(4),945–951 (2008).
16. Buchbinder SP, Mehrotra DV, Duerr A et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet372,1881–1893 (2008).
17. Frew PM, Mulligan MJ, Hou SI, Chan K, del Rio C. Time will tell: community acceptability of HIV research before and after the "Step Study" vaccine discontinuation. J. Clin. Trials2,149–156 (2010).
18. Newman PA, Yim S, Daley A et al. "Once bitten, twice shy": participants perspectives in the aftermath of an early HIV vaccine trial termination. Vaccine29(3),451–458 (2011).
19. Newman PA, Logie C, James L et al. "Speaking the dialect": understanding public discourse in the aftermath of an HIV vaccine trial shutdown. Am. J. Public Health101(9),1749–1758 (2011).
20. Essack Z, Koen J, Slack C, Lindegger G, Newman PA. Civil society perspectives on negative biomedical HIV prevention trial results and implications for future trials. AIDS Care doi:10.1080/09540121.656566 (2012) (Epub ahead of print).
21. Newman PA, Lee SJ, Rudy E et al. Preventive HIV vaccine acceptability and behavioral risk compensation among a random sample of high-risk adults in Los Angeles (L.A. VOICES). Health Serv. Res.44(6),2167–2179 (2009).
22. Blower SM, McLean AR. Prophylactic vaccines, risk behavior change and the probability of eradicating HIV in San Francisco. Science265,1451–1454 (1994).
23. Eaton LA, Kalichman SC. Risk compensation in HIV prevention: implications for vaccines, microbicides, and other biomedical HIV prevention technologies. Curr. HIV/AIDS Rep.4(4),165–172 (2007).

Website
101. UNAIDS Report on the Global AIDS Epidemic 2010. www.unaids.org/globalreport/Global_report.htm

Source

Challenges for HCV Vaccine Development in HIV–HCV Coinfection

From Expert Review of Vaccines

Mélanie Lambotin; Heidi Barth; Christiane Moog; François Habersetzer; Thomas F Baumert; Françoise Stoll-Keller; Samira Fafi-Kremer

Posted: 09/07/2012; Expert Rev Vaccines. 2012;11(7):791-804. © 2012 Expert Reviews Ltd.

Abstract and Introduction

Abstract

It is estimated that 4–5 million HIV-infected patients are coinfected with HCV. The impact of HIV on the natural course of HCV infection is deleterious. This includes a higher rate of HCV persistence and a faster rate of fibrosis progression. Coinfected patients show poor treatment outcome following standard HCV therapy. Although direct antiviral agents offer new therapeutic options, their use is hindered by potential drug interactions and toxicity in HIV-infected patients under HAART. Overtime, a large reservoir of HCV genotype 1 patients will accumulate in resource poor countries where the hepatitis C treatment is not easily affordable and HIV therapy remains the primary health issue for coinfected individuals. HCV vaccines represent a promising strategy as an adjunct or alternative to current HCV therapy. Here, the authors review the pathogenesis of hepatitis C in HIV-infected patients, with a focus on the impact of HIV on HCV-specific immune responses and discuss the challenges for vaccine development in HIV–HCV coinfection.

Introduction

HIV-1 and HCV may cause persistent infections with long-term high-level viremia in spite of a specific immune response.^[1] Both infections progress silently over several years, leading to the destruction of the immune system in the case of HIV-1 and liver cirrhosis in the case of HCV. Unlike HIV infection, HCV is spontaneously cleared in 25% of cases and curable in more than 50% of patients when treated with interferon (IFN)-based combination therapies.^[2,3] Coinfection is frequent because of the shared risk factors for viral transmission, as HCV and HIV are both transmitted through exposure to blood and sexual exposure, although with different efficiencies. Recent epidemiologic and clinical studies showed that the introduction of HAART has improved the survival of HIV-infected patients, while HCV-associated liver diseases have become a leading cause of death in the coinfected population. The standard treatment for HCV infection in HIV–HCV-coinfected patients is similar to that of HCV-monoinfected patients, although significant toxicity is associated with pegylated IFN-α and ribavirin in coinfected patients.^[4] Therefore, the development of new therapeutic and preventive strategies against HCV in HIV-infected individuals has become a priority. This review summarizes the current knowledge on the pathogenesis of hepatitis C in HIV-infected patients, with a focus on the impact of HIV on HCV-specific immune responses and discusses the challenges for HCV vaccine development in HIV–HCV coinfection.

Epidemiology of HCV in HIV-infected Individuals

More than 170 million individuals are chronically infected with HCV and 34 million people are living with HIV.^[201] It is estimated that 4–5 million HIV-infected patients are coinfected with HCV,^[5] with a predominance of HCV genotype 1 (50–80%).^[6–9] Population-based data on the global geographic distribution of HIV–HCV coinfection are largely unavailable. The prevalence of HCV coinfection among HIV patients is associated with HIV risk factors.^[5] The incidence of HCV is higher among injection drug users (IDUs; 72–95%),^[10,11] probably due to the high transmissibility of HCV through parenteral exposure, whereas only 10–15% of HIV-positive patients who are not IDUs are coinfected with HCV.^[5] However, several studies reported a rapid and significant rise in the incidence of HCV infection in HIV-positive non-IDU men who have sex with men (MSM), suggesting a sexual transmission of HCV.^[12–15] A longitudinal cohort study reported a tenfold increase in the incidence of HCV infections among HIV-positive MSM after the year 2000 in Amsterdam (from 0.18/100 to 0.87/100 people per year).^[13,14] Similar data were reported in London, where the estimated annual HCV incidence in HIV-positive MSM increased by 20% on average each year between January 2002 and June 2006.^[12,13] Unprotected and anal sex with multiple partners, along with the presence of sexually transmitted infections (e.g., syphilis), were reported in these populations, confirming the permucosal transmission of HCV infection.^[16] By contrast, the incidence of HCV infection remains low in HIV-negative MSM, heterosexuals with multiple partners and individuals at risk for sexually transmitted infections,^[17] suggesting that the HIV infection may increase the susceptibility to HCV infection and facilitate HCV sexual transmission. The increased vertical transmission of HCV was reported in mothers coinfected with HIV. A meta-analysis of observational studies demonstrated that the risk estimate (odds ratio) of HCV vertical transmission was 2.82 (95% CI: 1.78–4.45; p = 0.00001) from anti-HCV-positive/HIV-positive coinfected mothers as compared with anti-HCV-positive/HIV-negative mothers, suggesting that maternal HIV coinfection increased the risk of HCV vertical transmission.^[18] For these reasons, raising awareness and increasing screening are essential for preventing the transmission of HCV in HIV-infected individuals, especially among MSM.

Natural History of HCV Infection in HIV-coinfected Patients

HIV infection has deleterious effects on the natural history of HCV infection. After primary infection, approximately 25–30% of HCV-monoinfected patients spontaneously clear HCV, in comparison with only 15% of HIV–HCV coinfected patients.^[19] A prospective longitudinal study conducted involving 112 HIV–HCV coinfected patients showed that spontaneous HCV clearance was associated with a rapid decline in viral load, being 2.2 log₁₀ within 100 days versus 0.03 log₁₀ in the case of HCV persistence (hazard ratio: 1.78; p < 0.0001) and high CD4⁺ T-cell count.^[19] These data suggest that although coinfected individuals usually have persistent HCV infection, some are able to generate immunity against HCV and spontaneously clear the virus, indicating that HIV infection does not preclude vaccine-induced HCV-specific immunity.^[2]

During chronic HCV infection, HIV–HCV-coinfected patients exhibit a higher HCV RNA load and more rapid progression to cirrhosis compared with HCV-monoinfected patients. Moreover, an increased number of end-stage liver complications were found in coinfected patients over the last decade.^[20] In the French Germivic study, the rate of deaths related to HCV liver disease increased from 2 to 17% between 1995 and 2005.^[21]

The course of HIV-1 infection varies from one individual to another, ranging from spontaneous control of viral load without HAART to rapid depletion of CD4⁺ T cells and progression to AIDS. The patients (1–5%) who are able to maintain very low levels of plasma viral loads over long periods of time without antiretroviral therapy are known as 'HIV controllers' (normally <1000 HIV-1 RNA copies/ml) or 'elite controllers' (<50 HIV-1 RNA copies/ml). The mechanisms by which elite controllers naturally control HIV infection are not yet completely understood. Several studies showed that these patients exhibit an unusually robust HIV-specific T-cell response.^[22–24] However, the role of humoral immunity in the control of HIV replication is less clear, as neutralizing antibodies were found to be low in elite controllers. Moreover, non-neutralizing inhibitory antibodies were detected in elite controllers, these being correlated with low viral load or sustained CD4⁺ T-cell counts.^[25] Recently, a link between the natural control of HIV infection and improved control of HCV replication was suggested in two studies. An increased spontaneous clearance of HCV was reported in a cohort of African–American HIV controllers infected with HCV genotype 1,^[26] while a Spanish study suggested that Caucasian HIV controllers could better control HCV replication in terms of lower HCV viral load levels.^[27] However, the limitations of these studies include their low patient numbers and cross-sectional designs. In 2002, Alatrakchi et al. compared T-cell responses to HIV and HCV in HIV-infected long-term nonprogressors (defined in this study as individuals with a lack of disease progression and low HIV replication levels).^[28] These authors showed that, in addition to high Th1 cell frequencies directed against HIV-p24, long-term nonprogressors displayed significantly (p < 0.05) higher frequencies of Th1 cells against HCV as compared with HIV-positive progressors coinfected with HCV and HIV-negative HCV-infected patients. Immunological mechanisms by which HIV controllers partially control HCV infection deserve further investigations in order to develop future therapeutic strategies for HIV–HCV-coinfected patients.

Immunological Determinants of HCV Clearance

There is strong evidence that vigorous and sustained CD4⁺ and CD8⁺ T-cell responses against multiple HCV epitopes are associated with the spontaneous clearance of HCV infection.^[29] Patients who cleared HCV infection were shown to exhibit strong HCV-specific CD4⁺ T-cell responses during the acute phase of infection.^[30–33] By contrast, these responses were barely detectable in patients who subsequently developed persistent HCV infection.^[34,35] The relevance of the CD4⁺ T-cell response was also demonstrated in selective depletion experiments in HCV-infected chimpanzees. CD4⁺ T-cell depletion suppressed protective CD8⁺ T-cell immunity upon rechallenge, leading to HCV persistence.^[36] CD8⁺ T cells are the major effector cells of the antiviral response within the infected liver. The accumulation of HCV-specific CD8⁺ T cells in the liver coincides with the onset of liver disease and a rapid decline of viremia.^[37] There is also mounting evidence that neutralizing antibody responses contribute to HCV clearance and protection. Recent data obtained from a well-characterized homogenous cohort of patients exposed to a single inoculum of HCV demonstrated a direct correlation between HCV clearance during acute infection and the rapid induction of neutralizing antibodies.^[38,39] Furthermore, in vitro neutralization of the virus inoculum protected chimpanzees from HCV infection.^[40,41] In contrast to antibody titers that decline to undetectable levels in many patients after HCV clearance, HCV-specific memory T cells remain detectable for decades in the blood and liver.^[42,43] However, the occurrence of multiple episodes of HCV reinfection among individuals who are repeatedly exposed to HCV through injection drug use indicates that HCV-specific memory T cells are not sufficient to prevent HCV infection.^[44] Although this data suggests that sterilizing immunity is difficult to achieve, the reduced risk of developing persistent infection upon viral re-exposure in frequently exposed individuals and chimpanzees^[45] indicates that the immune system is able to develop a certain degree of protective immunity against HCV.^[46–50] Thus, the goal of current vaccine strategies is to maximize the HCV-specific immunity by stimulating strong and cross-reactive CD4⁺ and CD8⁺ T cells as well as neutralizing antibodies to increase the likelihood of HCV clearance and thereby reducing the risk of developing chronic hepatitis C.

Approximately 60–80% of HCV-infected patients are not able to clear the infection and so develop chronic hepatitis. Viral- and host-specific factors appear to contribute to viral evasion and the failure of the immune system to control HCV infection.^[29] First, HCV has a high rate of replication and lacks a proofreading function, thus allowing HCV to continuously escape the emerging cytotoxic CD8⁺ T-cell response and neutralizing antibody responses during chronic infection. Second, HCV-specific CD8⁺ T cells become functionally exhausted during chronic HCV infection, probably due to the constant HCV antigen stimulation. Third, HCV infection induces regulatory CD4⁺ T cells (Tregs), which are able to suppress HCV-specific effector T cells. It should be noted that in the case of HCV infection, the adaptive immune response induction is delayed for several weeks, which may be accounted for, by the tolerogenic environment of the liver^[51] and the fact that HCV has developed successful strategies to attenuate the host type I IFN-mediated innate response. IFNs not only exhibit potent antiviral activity but also induce adaptive immune responses. The genetic background of the host also has a significant impact on the outcome of HCV infection. The HLA class I allele B27 and class II allele DR11 were found to be associated with HCV clearance,^[52,53] suggesting the presence of protective HLA alleles. Of note, IL-28B polymorphisms, recently identified to be strongly associated with HCV treatment outcome, were shown to be significantly associated with spontaneous HCV clearance.^[54,55]

Once HCV persistence is established, spontaneous clearance without any therapy is a rare event.^[56] There have been reports of HCV clearance in the case of chronic infection after superinfection with other hepatitis viruses, such as hepatitis A, B or D,^[57–60] suggesting that heterologous T-cell immunity triggered HCV-specific immune responses.^[61] Preliminary insights into the immunological mechanisms leading to HCV clearance in the case of chronic HCV infection have been gained in a longitudinal study performed on a patient who spontaneously recovered from chronic HCV infection without any evidence of virus superinfection. In this report, HCV clearance was first associated with the appearance of neutralizing antibodies, followed by the reconstitution of HCV-specific T-cell immunity.^[62] These findings support the immunotherapy of chronic infections as they suggest that T-cell dysfunction is reversible and capable of clearing the infection.

Continue reading  here …

Hepatitis C patients petition for life-saving drug combination

by Wendy Rigby / KENS 5

Posted on June 28, 2012 at 3:26 PM Updated today at 3:59 PM

SAN ANTONIO -- South Texas patients with hepatitis C virus (HCV) have launched a petition to speed up development of some promising new drugs. They believe a pharmaceutical company is putting profits ahead of people.

Hepatitis C is a virus that attacks the liver. It’s the number one reason for liver transplants in the U.S. It kills more people than AIDS.

Margaret Dudley, 61, of San Antonio is a woman on a mission. More than a decade ago, she had permanent cosmetic tattooing. Last fall, she was tested for hepatitis C, a deadly disease she believes she contracted from the tattoos.

“You know, I had no idea,” Dudley said. “I had no reason to think it would come back positive, but it did.”

HCV hides out in the liver. Over the years, cysts form and scar tissue forms causing cirrhosis or hardening of the liver. Tumors can develop and the liver can fail.

Two promising pills from two different drug makers showed a 100 percent cure rate in early clinical trials when combined. GS-7977 is made by Gilead. Daclatasvir is from Bristol-Myers Squibb. But the companies have each invested millions and cannot agree on moving forward to get the winning combination to patients which could save their lives.

“So that’s basically what me and millions of others have been waiting for,” Dudley commented. “We started this petition asking Gilead Sciences to please go forward in these trials. We’re asking them to put best patient health before profits.”

Dudley has turned into a patient activist, using her voice to speak for four million Americans, mostly baby boomers, infected with this insidious disease.

She has 3,000 signatures on her online petition so far. She says public pressure may spark the pharmaceutical companies to keep going with clinical trials.

Dudley’s goal is to gather 100,000 signatures by July 28, 2012, which is World Hepatitis Day.

Source

Hepatitis B and Liver Cancer Among Asian Americans

By Jeffrey Norris on June 20, 2012

Liver cancer is expected to become more common in the United States in coming years. “It’s deadly and it’s preventable,” says UCSF physician and researcher Tung Nguyen, MD.

The cause of more than eight in 10 liver cancers in the United States is chronic infection with the hepatitis B or hepatitis C virus. Today the number of new hepatitis infections is declining. But just as there has been a lag between the decline in smoking and the drop in lung cancers, it may take many years before the trend toward fewer hepatitis cases and better hepatitis treatments leads to fewer liver cancers instead of more.

UCSF and Hepatitis

• Hepatitis — UCSF and San Francisco at Ground Zero
• Hepatitis C — Urgency to Fight Viral Foe Grows in the Suburbs and on the Streets
• Students Vaccinate Against Hepatitis B in Chinatown

Nguyen — who emigrated as a child from Vietnam — is fighting hepatitis in Bay Area Asian American communities. Through outreach and training of key community members and through campaigns in ethnic media, Nguyen and his collaborators aim to help reverse the US liver cancer trend as quickly as possible.

Hepatitis B Is Common

Why focus on Asian Americans? Hepatitis B is common in many parts of the globe, including Asia. Because of this, liver cancer is the third most common cause of cancer death worldwide. Immigrants from Asian countries are infected at high rates. So too are their children. For instance, in San Francisco, where according to the 2000 census nearly one in three people is Asian or of Asian ancestry, an estimated one in 10 Chinese is infected with hepatitis B.

Today in the United States, hepatitis C mainly is spread by IV drug users sharing needles. There is not yet a commercially available vaccine. On the other hand, there are vaccines to prevent hepatitis B infection. The vaccine strategy originated with pioneering research at UCSF. Children in the United States now are routinely vaccinated early.

But mothers can easily pass hepatitis B to their children in the womb. This is the major source of existing hepatitis infections in the U.S. Asian American community, Nguyen says. In addition, many children who immigrate to the United States miss school vaccinations and risk becoming infected later.

While most adults clear the hepatitis B virus without becoming chronically infected, most infants do not. Once infection becomes chronic, treatment can help control the virus, but chronic infection lasts a lifetime.

Only a minority infected with hepatitis go on to develop liver cancer. But because so many in Asian communities already are infected at birth, Nguyen explains, some are developing liver cancer in their 30s or even in their 20s. Increasing liver cancer screening among people who test positive for hepatitis is an important outreach goal, Nguyen notes.

Disease Is Often Symptomless

Hepatitis often has no symptoms. “Some people get vaccinated without getting tested first to see if they already have been infected,” Nguyen says. “They think they are protected, when in reality they already may be infected, and infecting others.”

In addition to serving on the President’s Advisory Commission on Asian Americans and Pacific Islanders, Nguyen is a partner in a San Francisco Department of Public Health program to combat hepatitis B. The aim of “San Francisco Hep B Free” is to screen, vaccinate and treat all Asians and Pacific Islanders who live in the city, in part by providing free or low-cost testing.

Nguyen also directs the Vietnamese Community Health Promotion Project through which he and his colleagues have targeted the community with messages via radio, television, print publications and online media. Vietnamese in the United States have the highest rate of liver cancer, about 11 times higher than the rate among whites.

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Idenix Announces Positive Clinical Data for HCV Drug Candidates IDX184 and IDX719

June 19, 2012

In an Interim Analysis From an Ongoing Phase IIb Clinical Trial of IDX184, an HCV Nucleotide Inhibitor, 89% of Patients Who Completed an Additional 12 Weeks of Pegylated Interferon Plus Ribavirin Treatment Achieved SVR4; 100% (4/4) in 100 mg Arm and 80% (4/5) in 50 mg Arm

IDX719, an HCV NS5A Inhibitor, Achieves Potent Pan-Genotypic Activity in Three-Day Proof-of-Concept Clinical Trial

CAMBRIDGE, Mass., June 19, 2012 (GLOBE NEWSWIRE) -- Idenix Pharmaceuticals, Inc. (Nasdaq:IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced results from an ongoing phase IIb study of IDX184 in combination with pegylated interferon and ribavirin (PegIFN/RBV). Of the first cohort of 31 patients enrolled in the study, those who achieved an eRVR (n=18), defined as having undetectable levels of virus at 4 weeks and 12 weeks, were randomized to stop treatment after either an additional 12 weeks (n=9) or 36 weeks (n=9) of PegIFN/RBV. Of the nine patients who completed their 12-week PegIFN/RBV extended treatment phase, 100% of patients (4/4) in the 100 mg arm and 80% of patients (4/5) in the 50 mg arm achieved a sustained virologic response four weeks after the completion of treatment (SVR4). Patients who did not achieve an eRVR automatically entered the 36-week PegIFN/RBV extended treatment phase which is ongoing. To date, the side effect profile of IDX184 combined with PegIFN/RBV is consistent with that of PegIFN/RBV alone.

"We are encouraged by the initial SVR results from the phase IIb program, which have confirmed previous data showing that IDX184 is a potent nucleotide inhibitor with a profile supporting its potential role as a key component of all-oral direct-acting antiviral (DAA) combination regimens for HCV," stated Ron Renaud, President and Chief Executive Officer of Idenix. "We look forward to initiating interferon-free DAA combination studies in the near term."

IDX184 Phase IIb Study Design

In July 2011, the company initiated enrollment of treatment-naive genotype 1 HCV-infected patients into a randomized, double-blind, parallel group phase IIb clinical trial of IDX184. The study features two treatment arms, either 50 mg or 100 mg of IDX184 administered once-daily for 12 weeks, each arm in combination with PegIFN/RBV. Response-guided therapy was used to complete an additional 12 or 36 weeks of PegIFN/RBV treatment. Study objectives include safety and tolerability, and antiviral activity endpoints.

IDX719 Proof-of-Concept Clinical Trial Data and Study Design

Idenix also announced today positive data from a three-day proof-of-concept study evaluating IDX719, an NS5A inhibitor, in 64 treatment-naïve, genotype 1, 2, 3 or 4 HCV-infected patients. Genotype 1 patients were randomized to receive placebo, 25 mg QD (once-daily), 50 mg QD, 50 mg BID (twice-daily) or 100 mg QD for three days. Genotype 2, 3 or 4 patients were randomized to receive placebo, 50 mg BID or 100 mg QD for three days.

IDX719 was well tolerated with no serious adverse events reported. Treatment with IDX719 exhibited potent pan-genotypic activity across genotypes:

• In genotype 1 patients (n=28), mean maximal viral load reductions were 3.2 log₁₀ IU/mL in the 25 mg QD arm, 3.7 log₁₀ IU/mL in the 50 mg QD arm, 3.2 log₁₀ IU/mL in the 50 mg BID arm and 3.5 log₁₀ IU/mL in the 100 mg QD arm.
• In genotype 2 patients (n=8), the mean maximal viral load reduction was 2.0 log₁₀ IU/mL in both the 50 mg BID and 100 mg QD dose arms with a greater variability in responses among these patients (range: 0.3 — 4.1 log₁₀ IU/mL). The company is currently conducting pharmacokinetic and sequencing analyses to further characterize these results.
• In genotype 3 patients (n=8), mean maximal viral load reductions were 3.3 log₁₀ IU/mL in the 50 mg BID arm and 3.4 log₁₀ IU/mL in the 100 mg QD arm.
• In genotype 4 patients (n=7), mean maximal viral load reductions were 3.9 log₁₀ IU/mL in the 50 mg BID dose arm and 3.4 log₁₀ IU/mL in the 100 mg QD dose arm.

More detailed findings are expected to be presented at a scientific meeting in the second half of 2012.

"We are pleased to demonstrate the first clinical validation of IDX719 in patients in a multiple-dose study with robust activity across multiple HCV genotypes," commented Douglas Mayers, M.D., Chief Medical Officer of Idenix. "Given these promising findings, we look forward to initiating a phase II combination study of IDX719 with IDX184 by the end of this year."

ABOUT IDX184

IDX184 is an unpartnered, novel, liver-targeted nucleotide prodrug of 2'-methyl guanosine, which includes Idenix's proprietary liver-targeting technology. This technology enables the delivery of nucleoside monophosphate to the liver, leading to the formation of high levels of nucleoside triphosphate, potentially maximizing drug efficacy and limiting systemic side effects with low, once-daily dosing. In the ongoing phase IIb clinical trial, IDX184 has been well tolerated with a side effect profile similar to that of PegIFN/RBV. In the first cohort of 31 patients, at 12 weeks in an intent-to-treat analysis, the complete early virologic response ( < 25 IU/mL at 12 weeks) was 93% for the 100 mg IDX184 arm (n=15) and 81% for the 50 mg IDX184 arm (n=16) of the study. The company completed enrollment of a second cohort of 36 additional patients in May 2012.

ABOUT IDX719

IDX719 is an NS5A inhibitor with low picomolar, pan-genotypic antiviral activity in vitro. In 36 healthy volunteers, IDX719 was safe and well tolerated at single doses of 5-100 mg as well as multiple doses of 100 mg for 7 days. Single doses of IDX719 demonstrated potent pan-genotypic antiviral activity in 18 genotype 1, 2 or 3 HCV-infected patients, with greater than 3 log₁₀ viral load reductions achieved in the 100 mg dose arm.

ABOUT HEPATITIS C

Hepatitis C virus is a common blood-borne pathogen infecting three to four million people worldwide annually. The World Health Organization (WHO) estimates that more than 170 million people worldwide are chronically infected with HCV, representing a nearly 5-fold greater prevalence than human immunodeficiency virus.

ABOUT IDENIX

Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical Company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix's current focus is on the treatment of patients with HCV. For further information about Idenix, please refer to www.idenix.com.

FORWARD-LOOKING STATEMENTS

This press release contains "forward-looking statements" for purposes of the safe harbor provisions of The Private Securities Litigation Reform Act of 1995, including but not limited to the statements regarding the Company's future business and financial performance. For this purpose, any statements contained herein that are not statements of historical fact may be deemed forward-looking statements. Without limiting the foregoing, the words "expect," "plans," "anticipates," "intends," "will," and similar expressions are also intended to identify forward-looking statements, as are expressed or implied statements with respect to the Company's potential pipeline candidates, including any expressed or implied statements regarding the efficacy and safety of IDX184 or IDX719 or any other drug candidate; the successful development of novel combinations of direct-acting antivirals for the treatment of HCV; the likelihood and success of any future clinical trials involving our drug candidates; and expectations with respect to future milestone or royalty payments, funding of operations and future cash balances. Actual results may differ materially from those indicated by such forward-looking statements as a result of risks and uncertainties, including but not limited to the following: there can be no guarantees that the Company will advance any clinical product candidate or other component of its potential pipeline to the clinic, to the regulatory process or to commercialization; management's expectations could be affected by unexpected regulatory actions or delays; uncertainties relating to, or unsuccessful results of, clinical trials, including additional data relating to the ongoing clinical trials evaluating its product candidates; the Company's ability to obtain additional funding required to conduct its research, development and commercialization activities; the Company's dependence on its collaboration with Novartis; changes in the Company's business plan or objectives; the ability of the Company to attract and retain qualified personnel; competition in general; and the Company's ability to obtain, maintain and enforce patent and other intellectual property protection for its product candidates and its discoveries. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. These and other risks which may impact management's expectations are described in greater detail under the heading "Risk Factors" in the Company's annual report on Form 10-K for the year ended December 31, 2011 and quarterly report on Form 10-Q for the quarter ended March 31, 2012, each as filed with the Securities and Exchange Commission (SEC) and in any subsequent periodic or current report that the Company files with the SEC.

All forward-looking statements reflect the Company's estimates only as of the date of this release (unless another date is indicated) and should not be relied upon as reflecting the Company's views, expectations or beliefs at any date subsequent to the date of this release. While Idenix may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, even if the Company's estimates change.

Source: Idenix Pharmaceuticals

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