October 3, 2010

New research reveals possible method for boosting the immune system to protect infants against HIV

October 3, 2010

- Researchers at Oregon Health &Science University may have uncovered a new weapon for combating HIV as it is passed from mother to newborn child. The research, which was led by researchers at OHSU's Oregon National Primate Research Center, will be published in the October 3rd online edition of the journal Nature Medicine.

"Mother-to-infant transmission of HIV is a tremendous worldwide problem, especially in several African nations," said Nancy Haigwood, Ph.D., researcher and director of the Oregon National Primate Research Center at OHSU.

According to the latest data from the World Health Organization, 33.4 million people were infected by the virus in 2008. About 67 percent of the world's infections are in African countries. In addition, 91 percent of the world's childhood infections are in Africa.

Haigwood, her colleagues at OHSU, along with researchers at the University of Washington are investigating strategies for preventing or countering HIV infections in babies born to women with HIV. Their strategy: to educate part of the baby's immune system within the first few hours of birth to better fight of the disease.

"HIV attacks and kills T-cells, the white blood cells that play an important role in the immune system because they have the ability to identify and destroy disease invaders. By attacking the body's natural defenses, the disease progresses, causes AIDS and eventually death," explained Haigwood. "Therefore, many therapies focus on protecting T-cells."

However, Haigwood and her colleagues took a different approach. They focused on another component of the immune system, which was initially thought to play a lesser role in the body's defense against HIV. Babies born to HIV-infected mothers have HIV-specific neutralizing antibodies at the time of birth that are "passively" acquired across the placenta. They wanted to determine whether boosted neutralizing antibody levels would weaken the disease's ability to overtake the body's defenses.

To investigate this possible treatment, the researchers studied three small groups of infant monkeys. The first group was given additional antibodies derived from healthy mothers. The second group was given antibodies matched to simian/human immunodeficiency virus (SHIV). SHIV is a hybrid virus used in research to ensure that results translate between species. The third group of animals was provided with HIV antibodies similar to, but not exactly matching, the strain of infection they would receive. The three groups were then exposed to SHIV and their immune systems were subsequently monitored.

Unlike the other two groups, the "HIV-matched" animals were better protected from the virus. They developed higher levels of neutralizing antibodies and, had lower levels of SHIV in their blood plasma than the comparison groups six months post-infection. In addition they maintained their CD4+ T cells - another component of the immune system.

The study also provided insights into the level of antibodies needed to impact disease progression. For this study, the antibody levels were relatively low dosed. Previously, antibodies were shown to block infection in animal models. This study demonstrated, for the first time, that very low levels of antibodies -- too low to block infection -- can influence disease progression in this setting and stimulate an immune response that contributes to viral control in the absence of drug treatment.

In future studies, the researchers hope to learn whether higher doses of antibodies translate into greater protection for the infants.

"This research demonstrates that boosting the body's HIV antibodies -- by a time-honored method of passive transfer that would use new HIV-specific human monoclonal antibodies -- may be a strategy for reducing infection levels and protecting CD4+ T cells in newborn children," said Haigwood. "While the treatment would not likely prevent infection, it could limit the levels of infection in children which would greatly reduce suffering and extend lives."

Provided by Oregon Health & Science University


New HCV Antivirals and Drug Resistance

Alan Franciscus, Editor-in-Chief
Lucinda K. Porter, RN
HCV Advocate

Researchers are investigating new antiviral medications to treat hepatitis C virus infection (HCV). Some of these drugs are referred to as direct antiviral medications since they specifically target the hepatitis C virus. However, unlike current HCV medications, direct antivirals carry the potential for resistance. This fact sheet will discuss the basics of HCV replication and why the hepatitis C virus becomes resistant to the newer drugs.

The Basics

Viruses are like rabbits; what they do best is multiply. The term for this is viral replication. However, a virus cannot survive on its own; it can only survive inside of another living cell, known as a host cell. Viruses use various pieces of the host cell’s genetic material in order to reproduce, or make more copies of itself. Viruses survive because of their ability to constantly adapt and change when they are under attack from the immune system. Viruses still try to reproduce even while under attack. In a hurry to escape, a virus may make a bad copy of itself, which slightly alters its genetic make-up. The process of change actually produces a variation in the virus, known as a mutation or quasi-species.

HCV acts like this. When you are newly infected, your immune system recognizes that an uninvited intruder (HCV) is in your body. Your immune system alerts your body to destroy HCV. However, HCV hurries to escape and makes a sloppy copy of itself, which outwits your immune system. Your immune system is patrolling for the original intruder, not realizing that the virus now looks a bit different. Now HCV can multiply at a faster rate. Eventually your immune system catches on and looks for the bad copy. In a hurry, HCV mutates again. This process may cycle through many, many mutations.

One way to think about this is with Darwin’s theory of evolution and survival of the fittest. In nature, the strong survive. The weak die and if they die before they reproduce, their weak genetic material dies too. In this way, it is more likely that strong genetic material is passed along. Evolution applies to plants, animals and microorganisms.

Current Therapies

The current standard of care for treating hepatitis C is a combination of pegylated interferon (long-acting) plus ribavirin therapy. How pegylated interferon works is not completely understood. What is known is this: 1) interferon boosts the ability of the body’s immune system to kill a virus, and 2) it protects noninfected cells from becoming infected. Interferon is used to treat a variety of diseases including hepatitis C.

We also do not understand how ribavirin works against HCV, but, when used with interferon, it seems to interfere with HCV’s ability to multiply, or replicate. Ribavirin alone is not effective against hepatitis C. When interferon and ribavirin are combined, there is a synergistic effect, which eliminates HCV in about half the people who take this combination. Synergy means that the combined total is greater than the sum of the separate parts.

Drug resistance does not develop with interferon and ribavirin since these drugs do not specifically target the enzymes of the virus used in the viral replication process. This means that treatment durations may vary in length and be tailored to patients’ needs. Patients may also undergo multiple treatments using the same drug(s). It is also the reason why people may interrupt or stop therapy without the development of drug resistance.

The HCV Replication Process and Direct Antivirals

The hepatitis C virus is a single-stranded RNA virus of the flavivirus family with a very rapid turnover or replication rate. HCV enters the body and targets the liver – the main replication site of HCV. The virus attaches itself to the outer coating of the liver cell or hepatocyte, and enters the cell. After entering the cell, HCV releases its genetic material and hijacks the cell’s internal processes.

Now that HCV has taken over, it binds to various ribosome sites within the cell. A ribosome is like a factory with printing presses. If a master copy of a document has a mistake in it, all of the copies will have that same mistake. This is referred to as translation. Drugs are being developed to interfere with this process, but so far, none have been found to be effective in stopping the translation process.

The next step involves an enzyme called the protease. HCV genetic material uses the protease enzyme to ‘cut up’ the genetic material into smaller pieces before additional viral processing. If this process is inter rupted, then the virus cannot make copies of itself. Protease inhibitors are exciting prospects in drug development to treat HCV since there are many potential protease enzymes involved in the replication process of the hepatitis C virus. The drugs in human clinical trial development that look the most promising are telaprevir and boceprevir.

Other materials that viruses depend on for replication are polymerase enzymes. HCV cannot multiply without these enzymes. Polymerase inhibitors are drugs used to stop this process . HCV polymerase inhibitors in human clinical trials include ABT-450 HCV, R7128, and PSI-938.

Viral replication relies on the helicase enzyme to complete the process. There are no HCV helicase inhibitors currently in development. Most experts believe that it will be difficult, if not impossible, to develop helicase inhibitors.

Resistance and Direct Antivirals

The new direct antivirals work by inhibiting the entry of the virus or by inhibiting the specific enzymes during one of the replication processes. The medications that look the most promising are the HCV protease and polymerase inhibitors. During the normal lifecycle of HCV, the body’s immune system exerts pressure on the replicating virus. This pressure produces mutations that escape the host’s immune response.

In a similar way, drugs to treat hepatitis C will exert pressure on the virus to change and mutate in order to survive. For this reason, it is believed that most of the direct antiviral medications will eventually produce drug resistant mutations, especially if these drugs are taken for a long time. This in turn may make the new medications ineffective in treating the new viral mutations.

Drug resistance is expected. However, scientists are looking for ways to prevent or interfere with drug resistance. For instance, drug resistant mutations may be identified earlier in the process, such as during the test tube development phase.

Preventing and Reducing Drug Resistance

The reduction or prevention of drug resistance depends on a number of factors. Some of these are:

Eradicating HCV: Unlike HIV and HBV, hepatitis C does not become part of the host cell. We have been able to rid HCV from the body with the use of current medications – pegylated interferon and ribavirin. In addition, HCV is an RNA virus. Since it does not integrate into the host cell’s DNA, as mentioned above, it will be easier to eliminate HCV without the risk of the virus changing or mutating.

Combination of direct and indirect antivirals: Direct antivirals can be given for a shorter period of time – this reduces the chances for the virus to ‘resist’ the drug. When used in combination with indirect antivirals – peginterferon and/or ribavirin, the chances of the virus developing resistance to the drug is lower. An example of this is extending the duration of treatment with peginterferon and/or ribavirin after stopping the direct HCV antiviral. This may prevent drug resistance while allowing for continual and hopefully complete viral suppression. For instance, telaprevir and boceprevir used in combination with pegylated interferon plus ribavirin have completed their phase III studies for people who have never been treated. It was found that treatment duration could be reduced for some people who responded to the new medications early on in treatment and that the total treatment duration could be reduced from 48 weeks to 24 or 36 weeks.

Potent direct antivirals: The development of potent direct antivirals that quickly distribute throughout the body and reach high blood concentrations in a short time period will put enough pressure on the virus before it has a chance to mutate. If the drugs are not potent enough, the escaped viral mutations may become the dominant virus, rendering the antiviral medication ineffective.

Combination direct antivirals: The use of direct antivirals that inhibit several different protease and/or polymerase enzymes at the same time will reduce the ability of the virus to mutate.

Adherence: Current HCV medications require adherence to prescribed doses and durations to be more effective in treating HCV. The new direct antivirals will require strict adherence. Doses that are skipped or forgotten could lead to viral mutations and drug resistance.

HCV research has benefited from what we know about HIV and HBV drug resistance and hopefully will be able to contribute to this body of knowledge. As we begin this era of new HCV medications, now is the right time to develop strategies to make HCV therapy more effective. Now is also the time to reduce the chances of the surfacing of drug resistance that could potentially reverse some of the benefits of new therapies. The best strategy for moving forward depends on using knowledge from the past in order to discover the future.

For more information about drugs in development to treat hepatitis C, visit our HCV Drug pipeline. www.hcvadvocate.org/hepatitis/hepC/HCVDrugs.html

For information about current clinical trial enrollment visit: http://www.clinicaltrials.gov/


Interferon- Vs. Non-Interferon-Based Therapy for Chronic Hepatitis B: Appropriate Patient Selection Is Key

One of the fundamental lessons we learn as medical providers is that the effectiveness and safety of drugs often vary between patients. Accordingly, patient selection may be key for making the best treatment decision. The stakes are even higher when drugs with predictable adverse effects are considered. All of these issues assume center stage when determining the type of antiviral therapy to treat hepatitis B.

Tolerability of antiviral therapy

Interferon accounts for no more than 10 percent of prescriptions for antiviral therapy in Europe and North America.1 The major reason for this is the inherently safer profile for nucleoside analogues and the need for less complex monitoring. It should be noted, however, that interferon-treated hepatitis B patients have better quality of life and improved tolerability than similarly treated patients with hepatitis C.2

Unfortunately, better patient acceptance with nucleoside analogues does not necessarily ensure better compliance, because as many as 30 percent of patients are not compliant with maintenance nucleoside analogue therapy.

Interferon is always contraindicated in patients with any level of liver decompensation due to flares of hepatitis and risk for serious infection. Practical experience indicates that interferon is less well tolerated in patients over the age of 60 and in those with significant co-morbid illnesses.

Differences in virologic response

Loss of hepatitis B surface antigen (HBsAg) is an important event, leading to improved outcomes and reduced rates of long-term complications.3 It is the closest one that comes to a clinical cure in hepatitis B.

Studies with standard or pegylated interferon have shown that 24 to 48 weeks of treatment accelerates the time to HBsAg loss. This occurs in a small number (3 percent to 5 percent) of hepatitis B cases initially, but prolonged follow-up demonstrates further gains in HBsAg clearance as long as durable hepatitis B virus (HBV) DNA suppression is maintained after treatment.4,5 By contrast, loss of HBsAg rarely occurs with nucleoside analogues, even with several years of therapy. Recent experience with tenofovir challenges this concept, but unlike the situation with interferon, HBsAg clearance has thus far been confined to non-Asians with hepatitis B virus e antigen (HBeAg)-positive hepatitis B. The reasons for the different kinetics of HBsAg clearance with the two classes of drug are not well understood, but the immunomodulatory effect of interferon is likely to play an important role.

The low rate of initial HBsAg clearance with both interferon and nucleoside analogue therapy has led to the use of “intermediate” efficacy endpoints such as sustained lowering of HBV DNA and HBeAg seroconversion. While “comparable” efficacy rates have been claimed, clinical extension trials of nucleoside analogues demonstrate that several years of treatment generally elapse before the rate of HBeAg seroconversion is equivalent (~30 percent) to that observed with interferon.

Patient selection

The efficacy of interferon, however, is very modest in HBeAg-positive cases with low alanine transaminase (ALT) (less than two times ULN) and high HBV DNA levels (greater than 200 million mIU/mL). In such cases, nucleoside analogue therapy is advisable. In my experience, it is also reasonable to use nucleoside analogue therapy as first-line treatment when baseline ALT is greater than or equal to five times ULN because this predicts a greater than 50 percent rate of HBeAg loss with one year of treatment.

Viral genotype is an especially important feature in determining the likelihood of response to interferon in HBeAg-positive hepatitis. Genotype A and B patients respond best and are more likely to lose not only HBeAg, but HBsAg. A treatment algorithm has recently been published by Janssen et al. that is based on the relationship between baseline patient features, viral genotype and the rate of HBeAg loss in a large number of pegylated interferon-treated cases.6 The accompanying table indicates what I have found to be the most important factors in my day-to-day experience.

Unfortunately, there are no clear-cut predictors of response in HBeAg-negative hepatitis B, a condition where relapse is frequent with 48 weeks of interferon or several years of nucleoside analogue therapy. The relationship between durable HBV DNA suppression off therapy and viral genotype is less well understood, but some studies have demonstrated that genotype D patients are especially difficult to treat. Ironically, HBsAg clearance has been demonstrated to occur in genotype D patients treated with pegylated interferon.6

Combination antiviral therapy

We do not know if pegylated interferon combined with newer nucleoside analogues such as entecavir or tenofovir results in a higher rate of durable viral suppression, HBeAg clearance or HBsAg clearance. Preliminary studies have suggested enhanced efficacy compared to previous studies using lamivudine. This may be due to the lower rates of resistance associated with newer agents. Ongoing treatment trials in HBeAg-positive and -negative hepatitis B, including one sponsored by the NIH (Hepatitis B Research Network, http://www.hepbnet.org/), will address this more definitively. Should significantly higher rates of response be found with combination therapy, it will be important to determine the baseline characteristics that predict a higher rate of response compared to either drug alone. Thus, patient selection is likely to remain key in the future as well, as better therapies are demonstrated. For me, hepatitis B is a condition where the old adage of “one size fits all” is likely to never apply.


1.Perrillo R. Benefits and risks of interferon therapy for hepatitis B. Hepatology 2009; 49:S103-11.

2.Marcellin P, Lau GK, Zeuzem S, et al. Comparing the safety, tolerability, and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alfa-2a. Liver Int 2008; 28:477-85.

3.Fattovich G, Giustina G, Sanchez-Tapias J, et al. Delayed clearance of serum HbsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP). Am J Gastroenterol 1998; 93:896-900.

4.Buster EH, Flink HJ, Cakaloglu Y, et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology 2008; 135:459-67.

5.Marcellin P, Bonino F, Lau GK, et al. Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2. Gastroenterology 2009; 136:2169-79.

6.Buster EH, Hansen BE, Lau GK, et al. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon alfa. Gastroenterology 2009; 137:2002-9.

Achillion to Present Multiple Posters at AASLD's The Liver Meeting 2010

ACH-1625 Protease Inhibitor Abstract Accepted as Late Breaking Poster

Growing Data Set Underscores Company's Significant HCV Franchise

NEW HAVEN, Conn., Sept. 15, 2010 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. /quotes/comstock/15*!achn/quotes/nls/achn (ACHN 2.96, -0.06, -1.99%) , a leader in the discovery and development of treatments for the most challenging infectious diseases, today announced that its abstract titled "ACH-1625 Demonstrates Sustained Viral Suppression in Presence of Uncommon Drug Resistant HCV Variants: Pharmacokinetic, Pharmacodynamic and Clinical Virology Analysis of Phase I Study" has been accepted as a late breaking poster presentation at the 61st Annual Meeting of the American Association for the Study of Liver Disease (AASLD) The Liver Meeting(R) 2010 being held October 29-November 2, 2010 in Boston.

Two additional abstracts on ACH-1625 titled "In Vitro Combination Studies of ACH-1625 (HCV NS3 Protease Inhibitor) and ACH-2928 (HCV NS5A inhibitor) in Presence and Absence of Ribavirin" and "Non-Clinical Studies to Assess Drug-Drug Interaction Potential of ACH-1625, a Clinically Effective HCV NS3 Protease Inhibitor" had previously been accepted for poster presentation.

In addition, an abstract on ACH-2684 titled "HCV NS3 Protease Inhibitor with Potent Activity against Multiple Genotypes and Known Resistant Variants" was previously accepted for poster presentation.

Achillion's late breaking poster will be displayed in the Late Breaking Poster Session on Monday, November 1 at 8:00 a.m. through the end of the day's session. The balance of the Company's posters will be displayed in the HCV Therapy: Preclinical and Early Clinical Development Poster Session on Tuesday, November 2 at 7:00 a.m. through the end of the day's session.

"The Liver Meeting 2010 is noteworthy for Achillion because, for the first time, we are presenting a significant amount of clinical data in support of our expanding HCV pipeline of products. The clinical data for ACH-1625 further supports this compound's potential to be a best-in-class therapy, and our pre-clinical data elucidate the potential for powerful combination therapies with our own drug candidates," noted Michael Kishbauch, President and Chief Executive Officer

"We were especially pleased to have our data selected for a Late Breaking poster as it underscores the importance of our positive clinical data with ACH-1625 to treat HCV since only a few such submissions were chosen for Late Breaking presentation. We look forward to sharing our positive results with the clinical and scientific audience at AASLD and to advancing ACH-1625 into Phase 2 studies this month."

About American Association for the Study of Liver Diseases

AASLD is the leading organization of scientists and healthcare professionals committed to preventing and curing liver disease. AASLD was founded in 1950 by a small group of leading liver specialists to bring together those who had contributed to the field of hepatology.

AASLD has grown to an international society responsible for all aspects of hepatology, and its annual meeting, The Liver Meeting(R), has grown in attendance from 12 to over 7,000 physicians, surgeons, researchers, and allied health professionals from around the world.

Hepatology has been recognized as a discipline only in the last few decades, and AASLD played a seminal and unifying role in focusing interest on hepatological problems, as well as the founding of other hepatological societies. AASLD organized the American Liver Foundation to educate the public about liver diseases.

About ACH-1625

ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50~1nM.

In clinical studies completed to date, subjects receiving both single and multiple ascending doses ranging from 50 mg to 2000 mg for periods up to 5 days demonstrated that ACH-1625 was well tolerated at all doses and there were no serious adverse events, no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.81og10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 2.0log10 from baseline through day 12, the last day of viral load measurement in the study.

About ACH-2684

ACH-2684 is a high potency protease inhibitor with potency in the picomolar range and activity against all HCV genotypes including highly-resistant strains of the HCV virus. The potency and virology profile of ACH-2684 demonstrates that it very effectively suppresses a broad range of natural variants of the hepatitis C virus, and may be effective in prevention and treatment of emerging resistant variants. This compound also retains potent activity against all genotypes.

About ACH-2928

ACH-2928, an NS5A inhibitor with potent activity against all genotypes, is highly effective in combination with NS3 protease inhibitors, NS5B polymerase inhibitors, interferon and ribavirin. In preclinical studies ACH-2928 has demonstrated excellent potency against HCV RNA replication, as well as good pharmacokinetic and safety profiles.

About Achillion

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease -- hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration; Achillion's expectations regarding timing and duration of other clinical trials, including additional dosing cohorts. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are uncertainties relating to results of clinical trials and unexpected regulatory actions or delays. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009.

All forward-looking statements reflect Achillion's expectations only as of the date of this release and should not be relied upon as reflecting Achillion's views, expectations or beliefs at any date subsequent to the date of this release. Achillion anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Achillion may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.

This news release was distributed by GlobeNewswire, http://www.globenewswire.com/

SOURCE: Achillion Pharmaceuticals, Inc.

CONTACT: Achillion Pharmaceuticals, Inc.
Mary Kay Fenton
(203) 624-7000
Lippert/Heilshorn & Associates, Inc.

Anne Marie Fields
(212) 838-3777

Bruce Voss
(310) 691-7100