HCV therapeutics: Times are changing

Infectious Disease News February 2012

by Robert T Schooley, MD

There are few areas in medicine in which the therapeutic landscape is poised to change more rapidly than in that for the therapy of hepatitis C infection. The 20 years after the introduction of interferon-alpha therapy witnessed only two advances in hepatitis C therapy.

First, ribavirin, an agent that had previously been pitched at more viruses than are included in most medical school curricula, was found to reduce the rate of relapse after a course of interferon-alpha therapy. Secondly, conjugation of interferon-alpha to polyethylene glycol was demonstrated to increase the chance of treatment and the tolerability of interferon therapy.

When these two modifications to classical interferon-alpha therapy were combined, a patient with HCV genotype-1 could look forward to a difficult year that resulted in a cure less than half of the time. In this situation, it would be expected that most patents reluctantly accepted therapy when they (and their physicians) came to the conclusion that therapy was required as a last effort to avoid end-stage liver disease or hepatocellular carcinoma.

In these circumstances, patients usually avoided therapy until their liver disease resulted in referral to a hepatologist who generally viewed their problem as a liver rather than a viral disease. We are now entering a new era in which therapeutic advances for HCV will completely change the treatment paradigm. This will be accompanied by much better outcomes for patients and will require a major expansion of the treating community in which HIV physicians will play a much greater role. These shifts will be driven by three major factors.

Success rates will increase

The addition of either of the newly approved HCV protease inhibitors — boceprevir (Victrelis, Schering) or telaprevir (Incivek, Vertex Pharmaceuticals) — to polyethylene glycol-interferon and ribavirin therapy has already increased the prospect of treatment success to about 70% in genotype-1 infection.

With the increased potency of three-agent antiviral regimens, treatment duration has decreased from 1 year to 6 months in most patients, and early assessment of the antiviral response can provide patients with prognostic information that is reliable as to whether a course of therapy is likely to be successful. Taken together, patients can expect treatment to be successful more frequently, and they will likely be inconvenienced for only half as long as before.

Furthermore, clinical trials with newer agents provide strong evidence that treatment success rates are poised to go higher and that courses of therapy will be shorter for many patients — and perhaps, most importantly, will ultimately include neither interferon nor ribavirin. These factors have already increased interest in testing for and treatment of HCV infection.

Initiation not driven by liver biopsy findings

As current therapies are limited in appeal, most patients seek therapy (and most physicians recommend therapy) only when liver disease has progressed to the point that cirrhosis is at hand or established. Although noninvasive approaches are emerging that serum markers or ultrasound are reasonably good at identifying patients with very little liver damage or substantial cirrhosis, liver biopsy is generally needed to provide sufficiently precise information in the middle spectrum of HCV-induced liver disease to make good therapeutic recommendations in most patients.

In addition, if therapy is delayed too long and decompensated cirrhosis has developed, interferon therapy can lead to liver failure and death. These factors have generally drawn hepatologists into the dialogue about whether therapy is indicated and usually keep them involved after therapy is started, if it is started later in the course of HCV-induced liver disease.

Decisions more complicated

Although art and science were involved in deciding when treatment should be recommended and when a patient should go through a course of polyethylene glycol-interferon/ribavirin therapy, the therapeutic landscape was reasonably straightforward once therapy was recommended.

Ribavirin was included in both regimens, and the two interferons differed from each other only in nuance. Thus, the treatment decision was a dichotomous one, and once therapy was started, side effects (though they were often substantial) were well delineated and predictable. In many treatment settings, a physician (usually a hepatologist) gathered the data and made recommendations about whether treatment was recommended, and care was actually delivered by physicians and nurse practitioners who were able to follow relatively simple toxicity management algorithms and manage most serious side effects with dose reduction and referrals to mental health workers for management of depression.

More than 20 directly acting anti-HCV agents are currently in various phases of development. These drugs have different molecular targets, resistance profiles, metabolic profiles, drug interactions and treatment durations — and it is clear that every regimen will require two to four of these new agents. As it becomes easier to decide who to treat, it is likely that more complex decisions will be required once therapy is started.

Decisions, not unlike those that the HIV-treating community has confronted for years, will be brought into the process, and “laminated-card driven” decision-making of the polyethylene glycol-interferon/ribavirin era will be a thing of the past. Decisions about overlapping resistance pathways and about interactions among anti-HCV agents (and between HCV agents and other drugs that patients must take) will be required. Because decisions about treatment duration and futility will be driven by close monitoring of antiviral response, multiple decisions will be required throughout the course of therapy. Although it is clear that these sorts of decisions can be made by hepatologists if they are heavily engaged in HCV therapy, it is likely that the hepatology community will see a further division into a subset of hepatologists who take care of hepatitis most of the time and a much larger subset who focus on transplantation and/or procedures.

Care models in new HCV therapy era

At present, there are approximately 4 million HCV-infected people in the United States, and it is estimated that fewer than 2,000 physicians are responsible for more than 80% of the currently administered antiviral therapy. As the number of those interested in HCV therapy increases and as the threshold to recommend therapy increasingly shifts to earlier stages of liver disease, current HCV treatment communities will become increasingly overrun. With a likely constriction in the number of hepatologists who are actively engaged in HCV therapy, it is clear that physicians from other disciplines will be drawn into HCV therapy.

Due to the complexity of HCV therapy, it will neither be good for patients nor an efficient use of resources to have thousands of generalists provide care to a few patients each. When HIV-1 emerged in the 1980s, AIDS “specialists” initially came from multiple training backgrounds, including internal medicine, infectious diseases, oncology, dermatology and family medicine.

As the field matured, most de novo training eventually became centered on infectious disease training programs. Most of the “primary” care for HIV (and many of us would also argue the best care) is now provided by multidisciplinary teams that are usually coordinated by physicians with infectious disease specialty training. These multidisciplinary teams optimally include those with complementary specialized expertise in the complications of the disease, including oncologists, hepatologists, psychiatrists, neurologists and clinical pharmacologists.

This shift occurred over time and with little explicit coordination or pre-cognition, but it has proved to be an extremely efficient model of care in which outcomes are better than in settings in which HIV care is provided by those with limited experience and expertise.

Rather than to stumble into an analogous model for HCV therapy during the next decade, it is attractive to think that the HIV experience could provide yet another window on the best approach to HCV care. Optimal HCV care will require interactive multidisciplinary teams with specialized expertise. Developing centers of excellence in HCV care should be a priority for the infectious disease community that should occur in anticipation of, rather than in response to, radically changing treatment paradigms.

These centers of excellence should also include hepatologists interested in viral hepatitis in their direction and operation and will need to include translational virologists, liver transplant surgeons, psychiatrists, radiologists with expertise in noninvasive imaging of the liver and clinical pharmacologists. Based on our experience in the medical and operational aspects of HIV infection, the infectious disease community must play a major role in the initial development of these centers, and most of the leaders in this exciting area of medicine should emerge from our training programs.

We’ve applied a lot of what we learned about RNA viruses from antiretroviral drug development to HCV drug discovery. Although it has been a bit slower, some of the lessons of the benefits of closely aligning clinical and translational science in drug development have been introduced into HCV drug development. There is no reason not to apply what we learned about optimal HIV care models to the very similar multidisciplinary landscape of HCV care.

Tremendous benefits will accrue to patients, and what could be more appealing to those of us in infectious diseases than a viral disease that we can actually eradicate — all that remains is to develop a billing code for “virectomy.”

Robert T. Schooley, MD, professor and head in the division of infectious diseases, and vice-chair of the department of medicine at the University of California, San Diego. Disclosure: Dr. Schooley is a member of scientific advisory boards for Gilead Sciences, GlobeImmune, Inhibitex, Johnson & Johnson, Monogram Biosciences, and Santaris. He has consulted for Merck. Research support is provided by Boehringer Ingelheim and Bristol-Myers Squibb.

Source

Is HCV Infection a Neurologic Disorder?

Download the PDF here

Gastroenterology March 2012
CYRILLE FERAY
Service d'HEpatogastroentErologie
Hotel-Dieu Hospital
Nantes, France

Hepatitis: Brain endothelial cells support HCV entry and replication - (01/27/12)

HCV SVR Improves Quality of Life & Brain Function - (01/27/12)

from Jules of NATAP: this topic of does HCV have a neurological effect & cause neurological symptoms has been controversial with many clinicians over the years doubting that this is true and with conflicting research, for example in HIV researchers have reported from studies not finding HCV caused cognitive impairment in HIV+ coinfected individuals. In the recent year or so there have been a number of research papers just like this finding that HCV enters the brain & can cause damage. There was research years ago from Pegasys studies showing improvement in neurological symptoms in patients achieving SVR. It is clear to me this is true. After achieving an SVR about 10 yrs ago I realized how much fatigue & cognitive impairment I had previously but before achieving the SVR I had no idea how much fatigue & cognitive impairment I had & I certainly did not appreciate it could be associated with HCV. After finishing HCV therapy & achieving an SVR the I started to feel improved energy & improved cognitive abilities. And over the next several years I experienced ongoing continuing further improvements. So there is no doubt that HCV can be associated neurological impairment and that it can improve. Now I had cirrhosis before achieving SVR so having a more severe stage of HCV disease may be more associated with experiencing cognitive impairment but I think earlier HCV disease can also be associated with fatigue, depression and cognitive impairment.

Hepatitis C is known to induce chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The absence of symptoms is common even when the disease has reached the stage of cirrhosis or hepatocellular carcinoma. For this reason, infection with hepatitis C virus (HCV) is frequently called a "silent killer." Fatigue is the most frequent complaint in infected subjects. HCV infection has also been associated with cognitive dysfunction and depression, which are not correlated with the severity of liver disease and cannot be explained by hepatic encephalopathy or drug abuse.

Numerous extrahepatic disorders have been attributed to or are more frequent during HCV infection. The most common mechanism underlying these disorders is autoimmunity. Thyroiditis, arthropathies, lymphocytic sialadenitis with or without sicca syndrome, and diabetes have long been known to be more frequent with HCV.1, 2 The second most frequent disorder associated with HCV infection is type II or III cryoglobulinemia. Cryoglobulins contain immune complexes made of HCV virions and anti-HCV antibodies and are highly prevalent in infected subjects. This can lead to symptomatic vasculitis with purpura, arthralgias, and asthenia, as well as peripheral nervous system and kidney involvement. Cryoglobulins are considered to be the result of B-cell proliferation owing to chronic antigenic stimulation, and B-cell lymphomas have been reported to be slightly more common in this population.3 A direct role of HCV is suggested by the fact that antiviral therapies have an antitumoral effect.4 The third group of extrahepatic symptoms associated with HCV infection could be a direct consequence of HCV infection of components of the central nervous system. Indeed, HCV RNA has been detected at autopsy in brain tissues.5, 6, 7, 8 Recently, an elegant study using microdissection in brain tissues from HCV-positive patients obtained at autopsy combined with measurement of cytokine mRNA in cells that were positive for the HCV nonstructural 3 protein suggested that brain macrophages/microglia cells were activated in HCV-infected patients.

The purpose of the paper by Fletcher et al,9 published in this issue of Gastroenterology, was to explore the original hypothesis that HCV could infect and alter the function of blood-brain barrier (BBB) endothelial cells. The authors first demonstrated that all of the known viral receptor molecules (CD81, claudin-1, occludin, LDLR, and scavenger receptor-B1) are expressed at the surface of BBB endothelial cells. It is important to note that scavenger receptor-BI expression was restricted to the microvascular endothelium, whereas other receptors were expressed by astrocytes. In a second step, the authors convincingly showed that HCV replicates in 2 distinct cell lines derived from these BBB endothelial cells. Hepatitis C is known to infect nonhepatocyte cells. There are numerous reports in the literature describing the presence of HCV RNA in immune cells10 as well as in the brain.11 In immune cells (mainly B-cells)12 and in the central nervous system,13, 14 the detection of viral sequences different from those found in the blood or the liver illustrates the compartmentalization of viral quasispecies and supports the idea that replication takes place in these extrahepatic sites. Indeed, in the absence of local replication, the presence of HCV RNA would be because of the adsorption or internalization of circulating viral particles produced in the liver; thus, no phylogenetic differences would exist with majority variants present in the serum (unless selection of liver-generated viral variants takes place at the cell receptor level). In almost all studies, the level of extrahepatic replication of HCV has been reported to be low, so that the contribution of these sites to circulating virions is limited. The HCV genome is positively stranded, meaning that it is directly translated into the viral polyprotein in the cell cytoplasm. The detection of negatively stranded HCV RNA in tissues or cells demonstrates that viral proteins have been translated and the HCV replication complex is functional, at least for the synthesis of negatively stranded HCV RNA. This intermediate of replication has frequently been detected in extrahepatic sites. There are, however, numerous technical issues that challenge the specificity of such detection. The detection of viral proteins in tissues or cells is also difficult because of their low level of expression. However, their presence has been convincingly reported recently in lymph nodes from the liver pedicle15 and in the brain.16

The most important information in the article by Fletcher et al9 is that human cell lines derived from BBB endothelial cells can be infected by HCV. The authors first tested HCV binding using HCV pseudoparticles (HCVpp) formed by the incorporation of the envelope glycoproteins E1 and E2 into lentiviral core particles. HCVpp closely mimic the functionality of wild-type viruses during the early steps of the viral lifecycle. HCVpp binding to endothelial cells was quantitatively similar to that observed with hepatocyte cell lines. The authors then used the JFH1 strain, the only HCV strain that effectively infects and replicates in primary human hepatocytes and in the hepatocyte cell line Huh7.5.17 Not surprisingly, HCV replicated at much lower levels in endothelial cells than in hepatocytes. Definitive confirmation of viral replication in endothelial cells was provided by using specific HCV protease inhibitors, which decreased the amount of HCV RNA in these cells. Micro-RNA (miR)-122 is hepatocyte specific and its fixation at 2 sites in the 5' untranslated region of the virus genome is required for efficient HCV replication. As expected, miR-122 was not detected in endothelial cell lines. The transfection of these cells to express functionally active miR-122 RNA duplexes failed to promote HCV replication, demonstrating that replication is miR-122 independent in endothelial cells. Indirectly, this result also suggested that liver-specific factors are required for the action of miR-122 on HCV replication in hepatocytes.

Another important group of findings in this paper was the observation of functional consequences of HCV infection of endothelial cells. Indeed, HCV increased endothelial cell permeability and this effect was reversed when replication was inhibited by antiviral molecules. Neutralization of HCV infection with pooled anti-HCV immunoglobulins also restored endothelial cell permeability, demonstrating the direct effect of HCV on this parameter. Furthermore, the authors noted that HCV-infected endothelial cell lines expressing nonstructural protein NS5A were TUNEL positive, suggesting an effect of infection on brain endothelial cell apoptosis. Altogether, these findings suggest that the infection of endothelial cells by HCV and HCV replication in these cells in vivo are highly plausible.

These findings raise the important question of the impact of HCV replication in BBB endothelial cells on neurocognitive and psychological symptoms frequently reported by subjects infected by this virus. This issue has been evaluated in case-control and in longitudinal studies assessing patients before and after a sustained virologic response to antiviral therapy. In these works, neurologic involvement was evaluated by means of neurocognitive tests combined with quality-of-life questionnaires or by measuring magnetic resonance spectroscopy (MRS) signals. Such case-control studies raise the issue of matching patients with HCV infection who know their status and have past or present addictive behaviors and HCV-negative controls. Despite these limitations, most studies reported more fatigue, more depression, and less effectiveness in HCV-infected patients than in controls. The longitudinal approach also has drawbacks. Subjects know the results of therapy and have experienced the adverse effects of antiviral drugs for many months. Although numerous studies have reported an improvement of the quality of life after achieving a sustained virologic response,18 only a few recent papers investigated changes in neurocognitive functions and MRS in relation to the response to therapy. The results of these studies are conflicting. In 1 study, the authors concluded that HCV eradication had a beneficial effect on cerebral metabolism and selective aspects of neurocognitive functions, especially in patients with mild disease.19 In contrast, another comparable study concluded that HCV had a measurable effect on brain integrity in patients screened for other medical and/or psychiatric comorbidities, but that these abnormalities did not improve after viral eradication.20 Both studies were based on a very small number of patients and the evaluation of neurocognitive functions and MRS were performed early after viral clearance. The second study20 questioned the reversibility of brain involvement once HCV infection is cured. Indeed, because brain cells have a very low rate of regeneration, the effect of HCV infection could be prolonged by months or years after the virus has been cured.

The main interest of the article by Fletcher et al9 is to show that the brain is a likely target for HCV. More important, the results with BBB endothelial cells suggest that other endothelial cells could be targeted and altered by HCV. For example, a study in an Egyptian population showed higher carotid intimal media thickness in HCV-infected than in noninfected patients.21 If this is confirmed, the possibility that HCV infection could induce brain or vascular disorders could modify the current indications for therapy, which are essentially based on the severity of liver disease or the presence of extrahepatic manifestations of immune origin, such as symptomatic cryoglobulinemia or B-cell lymphoma. Further studies are thus needed in the field of HCV neuroinvasion to better define the actual consequences of infection and their reversibility if infection is eradicated. However, it must be emphasized that the effects of HCV on neurocognitive functions, depression, or fatigue are generally mild. Many HCV-infected patients are highly successful and creative. Because stigmatization of HCV infected people exists, the notion of a brain involvement in these patients could have devastating consequences. The results of the present study should therefore be interpreted as what they are, certainly not overinterpreted as the demonstration that HCV infection leads to severe brain disease (Figure 1).

Source

TMC435-TiDP16-C212 - Trial of TMC435 in Genotype 1 Hepatitis C and Human Immunodeficiency Virus Co-Infected Patients

Provided by NATAP

This study is currently recruiting participants.

Verified February 2012 by Tibotec Pharmaceuticals, Ireland

Estimated Enrollment: 100

Drug: TMC435

150 mg capsule once daily for 12 weeks in addition to peginterferon alfa-2a and ribavirin for 24 or 48 weeks

First Received on October 18, 2011. Last Updated on February 27, 2012

Recruiting TMC435-TiDP16-C212 - Trial of TMC435 in Genotype 1 Hepatitis C and Human Immunodeficiency Virus Co-Infected Patients

This is an open-label (all people know the identity of the intervention) study of TMC435 in patients who are infected with genotype 1 hepatitis C virus and co-infected with human immunodeficiency virus (HIV). Patients in this study will also receive two other drugs for their hepatitis C infection called peginterferon alfa-2a and ribavirin. The purpose of the study is to investigate the safety, tolerability, and efficacy of TMC435 against hepatitis C virus in this patient population. For the first 12 weeks all patients will receive TMC435 plus peginterferon alfa-2a and ribavirin. For the subsequent 12 weeks, patients will take peginterferon alfa-2a and ribavirin only. After that, based on prior HCV treatment experience and prespecified on-treatment response criteria, some patients will continue to take peginterferon alfa-2a and ribavirin for total treatment duration of 48 weeks. The study doctor will inform each patient about how to take their study medication and when they should stop taking it. Patients will take their own regimen of HIV medication(s) throughout the study, according to the instructions of the study doctor. After a patient stops taking study medication, they will continue to come to the study doctor's office for study visits for up to 72 weeks after they received the first dose of treatment in the study. The maximum duration of the study is 81 weeks (including screening). Patients will be monitored for safety throughout the study. Study assessments at each study visit may include, but are not limited to: blood and urine collection for testing and physical examinations.

Importance of Pharmacokinetics and Adherence to Avoid Emergence of Resistant HCV Variants

Jean-Michel Pawlotsky, MD, PhD
Professor, Department of Virology
Henri Mondor Hospital
Université Paris Est
Créteil, France

Introduction

Hepatitis C virus (HCV) resistance to a direct-acting antiviral (DAA) agent corresponds to the selection during treatment of viral variants that bear amino acid substitutions that alter the drug target; therefore, they are less susceptible to the inhibitory activity of the drug. These drug-resistant variants preexist as minor populations within the patient’s HCV quasispecies. Drug exposure profoundly inhibits replication of the dominant “wild-type” drug-sensitive viral population, and the resistant variants gradually occupy the vacant replication space. Moreover, viruses with low-level or partial resistance that can continue to replicate in the presence of drug, often favored by suboptimal drug exposure, may accumulate further mutations, leading to stepwise decreases in drug susceptibility, albeit often at a cost of reduced replicative capacity. If insufficient antiviral activity is provided because of suboptimal dosing or adherence, inadequate virologic suppression and the selection of resistance is inevitable. Therefore, to reduce the development of resistance, it is essential to achieve optimal drug concentrations through proper dosing and maximal adherence.

Factors That Influence Viral Resistance in vivo

In vivo, viral resistance is influenced by 3 major related factors: the genetic barrier to resistance, the in vivo fitness of the resistant viral population, and drug exposure.^[1]

The genetic barrier to resistance is defined as the number of amino acid substitutions needed for a viral variant to acquire full resistance to the drug in question. If a single substitution is sufficient to confer high-level resistance to a specific drug, the drug is considered to have a low genetic barrier to resistance, whereas 3 or more substitutions are required to confer resistance to a drug with a high genetic barrier. There is a low likelihood that variants bearing a large number of resistance substitutions will preexist in a given patient and be fit enough to replicate at high levels when an antiviral drug is administered. Therefore, drugs with a high genetic barrier to resistance are less likely to be associated with clinically meaningful resistance.

The in vivo fitness of the viral variant is defined as its ability to survive and grow in the replicative environment. A selected resistant variant must have the capacity to propagate to fill in the replication space left vacant by the elimination of a susceptible wild-type virus during drug exposure. Thus, a highly resistant but poorly “fit” virus will be less clinically significant than a less resistant but “fitter” virus that can replicate efficiently in the presence of the drug. The acquisition of compensatory mutations may restore the fitness of a resistant variant and allow it to replicate efficiently in the presence of the drug, possibly allowing it to persist after drug withdrawal.

Finally, drug exposure affects the development of drug resistance. The degree of drug resistance of a variant can be measured in vitro as the fold increase in the 50% and 90% inhibitory concentrations (IC₅₀ and IC₉₀ in cell-free assays) or the 50% and 90% effective concentrations (EC₅₀ and EC₉₀ in cell-culture systems), that is, the drug concentrations that inhibit the tested enzyme function or viral replication by 50% and 90%, respectively. Drug exposure is defined as the drug concentration achieved in vivo relative to the IC₅₀, IC₉₀, EC₅₀, or EC₉₀ of resistant variants. This measurement is a key determinant of the development of resistance in vivo. Indeed, if drug levels achieved in vivo are far above these IC/EC values, then resistant variants will be effectively inhibited even if they are far less susceptible than the wild-type virus in vitro. Therefore, the pharmacokinetics of the antiviral drugs and adherence to therapy are key in preventing treatment failure due to viral resistance.

Importance of Pharmacodynamics/Adherence to Interferon-Containing DAA Regimens

The importance of achieving high blood DAA concentrations to prevent the emergence of resistance was demonstrated in the first phase Ib trial with telaprevir, an NS3/4A protease inhibitor (PI) with a low genetic barrier to resistance, administered as monotherapy for 14 days.^[2] In this trial, patients were more likely to achieve either an HCV RNA plateau or virologic breakthrough during the dosing period due to selection of telaprevir-resistant variants if they received lower telaprevir doses (450 mg every 8 hours or 1250 mg every 12 hours) than if they received the higher dose (750 mg every 8 hours).^[2] However, outgrowth of resistant viral populations was only delayed in the latter group. In vivo fitness assessments showed that less resistant, but “fitter” variants were more likely to become the dominant species than more resistant, less “fit” HCV variants.^[2] These findings led the American and European regulatory agencies to limit monotherapy studies involving DAAs with low genetic barriers to resistance to only a few days. Therefore, no other studies provided sufficiently long administration to accurately assess the effect of drug exposure on the emergence of resistance.

Resistance to antiviral drugs is classically prevented by combining several drugs with potent antiviral activity and no cross-resistance. Indeed, HCV resistance to DAAs is observed significantly less frequently when one of these drugs is administered in combination with peginterferon and ribavirin.^[3,4] Therefore, the triple combination of peginterferon, ribavirin, and a PI—telaprevir or boceprevir—has become the new standard-of-care therapy for both treatment-naive and treatment-experienced patients with genotype 1 HCV infection.^[5-8] For the reasons defined above, it is crucial that optimal exposure to all 3 drugs in the regimen be achieved for these patients. Telaprevir must be taken at a dose of 750 mg every 8 hours with fatty food, whereas boceprevir must be taken at the dose of 800 mg every 8 hours with food. Patients must fully adhere to the regimen for the entire treatment period because any prolonged interruption in PI administration would inevitably result in a resurgence of wild-type viruses and the opportunity for resistant variants to acquire fitness, especially if the antiviral pressure exerted by peginterferon and ribavirin is only modest. However, if the patient does miss a dose of telaprevir or boceprevir, the package inserts provide guidance on how to manage these short interruptions. For telaprevir, the prescribing information recommends that a missed dose should be skipped if more than 4 hours have passed since the time it is usually taken; however, if it is within 4 hours of the time that it is usually taken, the missed dose should be taken immediately with high-fat food.^[5,6] The recommendation for boceprevir is similar, but the timing is different. A missed boceprevir dose should be skipped if it is fewer than 2 hours before the next dose is scheduled; if it is more than 2 hours before the next scheduled dose, the missed dose should be taken immediately with food.^[7,8]

The importance of adherence to peginterferon and ribavirin has been demonstrated in the absence of DAAs; these data showed that optimal response rates were observed in patients who achieved more than 80% of their prescribed peginterferon and ribavirin doses for more than 80% of the time.^[9] The impact of poor adherence to, or dose reductions of, peginterferon, ribavirin, or both has not been extensively studied in clinical trials with the triple combination of peginterferon, ribavirin, and telaprevir or boceprevir. Nevertheless, maintaining the dose of peginterferon is likely to be key in interferon-responsive patients treated with triple therapy because treatment failure primarily results from an inadequate response to peginterferon, leading to the uncontrolled outgrowth of resistant variants selected by the PI.^[1,10-12] By contrast, a retrospective analysis of patients completing 48 weeks of peginterferon/ribavirin therapy suggested that reducing the dose of ribavirin has a negative impact on the outcome of therapy only before HCV RNA becomes undetectable, whereas the impact is modest after HCV replication is controlled.^[13] More recent studies in patients receiving PI-based therapy have shown that modest ribavirin dose reductions do not impair the likelihood of treatment success.^[14,15] Finally, a recent study showed that the cost effectiveness of triple therapy is dependent on optimal adherence.^[16]

There are several strategies that can be used to optimize adherence rates in patients receiving DAA-based therapy, some of which are under investigation. Current strategies include patient education on the importance of adherence, interventions to reduce the adverse effects of therapy, addressing comorbidities that may affect adherence to therapy, and using a multidisciplinary team to help physicians implement all of the aforementioned strategies. Regarding patient education, a prospective, multicenter study was conducted to determine the influence of patient education on adherence to peginterferon plus ribavirin therapy in patients infected with HCV.^[17] Investigators showed that patient education can significantly influence adherence to treatment as evidenced by adherence rates to ribavirin of 56% at 6 months in 175 patients not receiving education vs 70% in 208 patients receiving education (P = .006).^[17] Therapeutic education included intervention by healthcare professionals other than the prescribing physician as well as the distribution of support documents and educational materials. Another study found that physician’s treatment experience and patient motivation were associated with improved adherence to HCV therapy, indicating that empowering patients to take charge of their own treatment can impact adherence.^[18] It should be noted, however, that no data are yet available on how these strategies may affect adherence to triple combinations with the HCV PIs.

Importance of Pharmacodynamics/Adherence to Interferon-Free DAA Regimens

Maintaining optimal adherence has been shown to be an extremely effective way of minimizing the development of resistance in the HIV field.^[19] Strategies under investigation that may help optimize adherence rates to interferon-free DAA therapy include less frequent dosing and ritonavir boosting. Many DAA agents in development have half-lives that may allow for twice- or even once-daily dosing, which is encouraging.

In HIV therapy, the use of low-dose ritonavir to improve the pharmacokinetics of HIV PIs (so-called ritonavir boosting) has become standard practice. NS3/4A PIs are cytochrome P450 3A substrates; therefore, their plasma concentrations can also be substantially improved when coadministered with low-dose ritonavir, which may allow for prolonged dosing intervals and subsequent increased adherence rates. Boosting has been studied with 3 PIs—danoprevir, narlaprevir, and ABT-450—with encouraging results that suggest such strategies may support once-daily dosing, reduce adverse events (by lowering the required dose of the HCV PI), and reduce the risk of resistance.^[20-23] Results with ABT-450 showed that higher plasma trough levels were associated with a lower likelihood of selecting resistant HCV variants over a short course of administration of 3 days.^[23] However, a number of first-generation PIs can achieve high and well-tolerated plasma concentrations with once- or twice-daily dosing without ritonavir boosting.

Interferon-free regimens will reduce toxicity and adverse effects associated with peginterferon and ribavirin therapy, possibly improving adherence rates. The results of a short-term study combining the NS3/4A PI GS-9256 and the nonnucleoside RNA-dependent RNA polymerase inhibitor tegobuvir has been disappointing because this combination of agents has a low genetic barrier to resistance and frequent early virologic breakthroughs were observed.^[24] Additional studies which have combined agents with low genetic barriers to resistance include the SOUND-C1 and SOUND-C2 studies. These trials combined the NS3/4A protease inhibitor BI 201335 and nonnucleoside polymerase inhibitor BI 207127, with or without ribavirin.^[25,26] The ZENITH study combined the NS5B polymerase inhibitor VX-222 plus telaprevir.^[27] In the SOUND-C2 study, treatment response rates, and likely the selection of resistant HCV variants, appeared to be influenced by the genetic background of the host (IL28B genotype).^[26] Regimens comprising agents with higher barriers to resistance, such as the cyclophilin inhibitor alisporivir,^[28] the combination of the nucleoside analogue inhibitor mericitabine and the PI danoprevir,^[29] and the combination of the nucleotide inhibitor PSI-7977 with ribavirin have shown more promising results.^[30] Indeed, the latter combination resulted in undetectable HCV RNA at 12 weeks post-therapy (SVR12) for 10 out of 10 genotype 2/3 HCV–infected treatment-naive patients receiving this regimen for 12 weeks.

Another interferon-free regimen comprising agents with low barriers to resistance—the first-generation NS3/4A PI asunaprevir and the NS5A inhibitor daclatasvir—has provided valuable information on the importance of drug exposure and how this differs depending on HCV subtype.^[31,32] Protease inhibitors have a low genetic barrier to resistance; they can select fit variants that are poorly controlled at the drug concentrations achieved by doses used in clinical trials and practice. This is also true for NS5A inhibitors in genotype 1a HCV, as suggested by in vitro by studies showing a major shift in the IC₅₀s induced by single amino acid substitutions in the NS5A sequence.^[33] As a result, virologic breakthrough due to the selection of HCV variants resistant to both drugs was observed within a few days to weeks in 6 of the 9 patients infected with genotype 1a HCV.^[31] By contrast, in genotype 1b HCV models in vitro, daclatasvir retains subnanomolar potency against all variants with single amino acid substitutions; the fold-change in IC₅₀s conferred by these substitutions in the presence of the inhibitor was substantially lower than in genotype 1a.^[33] Consequently, the drug concentrations achieved in vivo in genotype 1b HCV–infected patients were able to control NS5A variants carrying these substitutions, both in the absence or presence of associated substitutions conferring resistance to the PI. As a result, the combination of asunaprevir and daclatasvir was shown to lead to high sustained viral eradication rates (~ 90%) in patients infected with genotype 1b HCV.^[31,32] To date, the available data on interferon-free regimens are more informative regarding pharmacodynamics and exposure than adherence. Additional data are awaited.

Conclusions

Although data are scarce regarding drug exposure and adherence in the context of HCV treatment with new DAA-based therapies, preliminary data and lessons learned from the HIV field suggest that optimal drug exposure and maximal adherence will be crucial to success with DAA-based therapies. In addition, the data from interferon-free regimens emphasize the importance of drug exposure, through optimal dosing and strict adherence to the prescribed regimen, when using combinations of drugs with a low to moderate barrier to resistance. Drugs with a higher barrier to resistance, such as nucleos(t)ide analogues, cyclophilin inhibitors, or second-generation PIs may theoretically be more tolerant to weaker adherence, but data are lacking thus far. When these therapies are available in clinical practice, virologic failures may be observed more often than in strictly controlled clinical trials. Vigilance and thorough patient education will be required to ensure high cure rates.

References

1. Pawlotsky JM. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology. 2011;53:1742-1751.

2. Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology. 2007;132:1767-1777.

3. Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360:1839-1850.

4. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360:1827-1838.

5. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.

6. Incivo [telaprevir]. European Medicines Agency. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002313/WC500115529.pdf. Accessed February 16, 2012.

7. Victrelis [package insert]. Whitehouse Station, NJ: Merck & Company; 2011.

8. Victrelis [boceprevir]. European Medicines Agency. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002332/WC500109786.pdf. Accessed February 16, 2012.

9. McHutchison JG, Manns M, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002;123:1061-1069.

10. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.

11. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217.

12. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.

13. Reddy KR, Shiffman ML, Morgan TR, et al. Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment. Clin Gastroenterol Hepatol. 2007;5:124-129.

14. Sulkowski MS, Poordad F, Manns MP, et al. Peginterferon alfa-2b/ribavirin with or without boceprevir is associated with higher SVR rates: analysis of previously untreated and previous treatment-failure patients. Program and abstracts of the 46th Annual Meeting of the European Association for the Study of the Liver; March 30 - April 3, 2011; Berlin, Germany. Poster 476.

15. Poordad F, Sulkowski MS, Reddy R, et al. Anemia had no effect on efficacy outcomes in treatment-naive patients who received telaprevir-based regimens in the ADVANCE and ILLUMINATE phase 3 studies. Program and abstracts of the Digestive Disease Week; May 7-10, 2011; Chicago, Illinois. Abstract 626.

16. Shan Liu SM, Cipriano LE, Holodniy M, et al. New protease inhibitors for the treatment of chronic hepatitis C. Ann Intern Med. 2012;156:279-290.

17. Cacoub P, Ouzan D, Melin P, et al. Patient education improves adherence to peg-interferon and ribavirin in chronic genotype 2 or 3 hepatitis C virus infection: a prospective, real-life, observational study. World J Gastroenterol. 2008;14:6195-6203.

18. Tanioka D, Iwasaki Y, Araki Y, et al. Factors associated with adherence to combination therapy of interferon and ribavirin for patients with chronic hepatitis C: importance of patient's motivation and physician's treatment experience. Liver Int. 2009;29:721-729.

19. Mocroft A, Phillips AN, Soriano V, et al. Reasons for stopping antiretrovirals used in an initial highly active antiretroviral regimen: increased incidence of stopping due to toxicity or patient/physician choice in patients with hepatitis C coinfection. AIDS Res Hum Retroviruses. 2005;21:743-752.

20. Gane E, Rouzier R, Stedman C, et al. Ritonavir boosting of low dose RG7227/ITMN-191, HCV NS3/4A protease inhibitor, results in robust reduction in HCV RNA at lower exposures than provided by unboosted regimens. Program and abstracts of the 45th Annual Meeting of the European Association for the Study of the Liver; April 14-18, 2010; Vienna, Austria. Abstract 38.

21. Rouzier R, Larrey D, Gane EJ, et al. Activity of danoprevir plus low-dose ritonavir (DNV/R) in combination with peginterferon alfa-2a (40KD) plus ribavirin (PEGIFNα-2A/RBV) in previous null responders. Program and abstracts of the 46th Annual Meeting of the European Association for the Study of the Liver; March 30 - April 3, 2011; Berlin, Germany. Abstract 62.

22. de Bruijne J, Bergmann JF, Reesink HW, et al. Antiviral activity of narlaprevir combined with ritonavir and pegylated interferon in chronic hepatitis C patients. Hepatology. 2010;52:1590-1599.

23. Pilot-Matias T, Tripathi R, Dekhtyar T, et al. Genotypic and phenotypic characterization of NS3 variants selected in HCV-infected patients treated with ABT-450. Program and abstracts of the 46th Annual Meeting of the European Association for the Study of the Liver; March 30 - April 3, 2011; Berlin, Germany. Abstract 1229.

24. Zeuzem S, Buggisch P, Agarwal K, et al. The protease inhibitor GS-9256 and non-nucleoside polymerase inhibitor tegobuvir alone, with RBV or peginterferon plus RBV in hepatitis C. Hepatology. 2011;[Epub ahead of print].

25. Zeuzem S, Asselah T, Angus PW, et al. High sustained virologic response following interferon-free treatment of chronic HCV GT1 infection for 4 weeks with HCV protease inhibitor BI201335, polymerase inhibitor BI207127 and ribavirin, followed by BI201335 and pegIFN/ribavirin—the SOUND-C1 study. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 249.

26. Zeuzem S, Soriano V. Asselah T, et al. Virologic response to an interferon-free regimen of BI 201335 and BI 207127, with and without ribavirin, in treatment-naive patients with chronic genotype-1 HCV infection: Week 12 interim analysis of the SOUND-C2 study. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract LB15.

27. Nelson DR, Gane EJ, Jacobson IM, et al. VX-222/telaprevir in combination with peginterferon-alfa and ribavirin in treatment-naive genotype 1 HCV patients treated for 12 weeks: ZENITH study, SVR12 interim analysis. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract LB14.

28. Pawlotsky JM, Flisiak R, Rasenack J, et al. Once-daily alisporivir interferon (IFN)-free regimens achieve high rates of early HCV clearance in previously untreated patients with HCV genotype (G) 2 or 3. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract LB11.

29. Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2010;376:1467-1475.

30. Gane EJ, Stedman CA, Hyland RH, et al. PSI-7977: ELECTRON. Interferon is not required for sustained virologic response in treatment-naive patients with HCV GT2 or GT3. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 34.

31. Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med. 2012;366:216-224.

32. Chayama K, Takahashi S, Kawakami Y, et al. Dual oral combination therapy with the NS5A inhibitor daclatasvir (DCV; BMS-790052) and the NS3 protease inhibitor asunaprevir (ASV; BMS-650032) achieved 90% sustained virologic response (SVR12) in Japanese HCV genotype 1b–infected null responders. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract LB4.

33. Fridell RA, Qiu D, Wang C, Valera L, Gao M. Resistance analysis of the hepatitis C virus NS5A inhibitor BMS-790052 in an in vitro replicon system. Antimicrob Agents Chemother. 2010;54:3641-3650.

Source

Does Coffee Really Protect Against Liver Fibrosis?

From Medscape Gastroenterology > Ask the Experts

William F. Balistreri, MD

Posted: 03/02/2012

Question:

I heard a report that coffee may protect against liver fibrosis in patients with fatty liver disease -- is it true?

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

Coffee and Fatty Liver Disease

That report likely refers to a recent study in which investigators attempted to correlate coffee (caffeine) consumption with the severity of nonalcoholic fatty liver disease (NAFLD).^[1] As Malloy and colleagues point out, an association between coffee consumption and a reduced risk for liver disease progression was established years ago.^[2-5] Coffee intake has been shown to correlate with lower liver enzyme levels and a reduced risk for hospitalizations and mortality in patients with cirrhosis. A recent example: Coffee consumption was linked to lower rates of clinical and pathologic progression of liver fibrosis in patients with chronic hepatitis C infection.^[6]

Investigators at Brooke Army Medical Center in Fort Sam Houston, Texas,^[1] therefore, questioned whether coffee ingestion by patients with NAFLD would similarly slow the progression of liver disease from steatosis to nonalcoholic steatosis (NASH). In their study, more than 300 patients underwent liver ultrasound; those in whom the ultrasound was negative for fatty liver served as controls. Patients with steatosis suggested by ultrasound underwent liver biopsies to categorize the patients into 3 groups:

• Bland steatosis without evidence of NASH;
• NASH with stage 0-1 fibrosis; and
• NASH with stage 2-4 fibrosis.

A validated questionnaire was used to determine whether a relationship existed between caffeine consumption (assessing the average mgs of total caffeine/coffee per day) and the degree of steatosis/NASH. A negative relationship was found between caffeine/coffee consumption and the degree of hepatic fibrosis. A significant difference in caffeine/coffee consumption was found between patients who had bland steatosis compared with those who had NASH stage 0-1, as well as between patients who had NASH stage 0-1 compared with those who had NASH stage 2-4. Therefore, this study demonstrates a histopathologic correlation between progression of fatty liver disease and estimated coffee intake. In their cohort of patients with NASH, increased intake of coffee seemed to confer a significantly reduced risk for advanced fibrosis. What is not clear from their data is the amount of coffee or caffeine that must be ingested to lower the risk for fibrosis. Also, because the study was not prospective, the impact of the observed effects on clinical outcomes over time is unknown. Further prospective studies are required.

What Is the Mechanism?

Assuming that the beneficial effects are real, what is the mechanism? Does coffee intake have a direct effect -- attributable to caffeine or to "magical powers of the bean"? Or is the effect indirect -- related to the preferential intake of coffee as a substitute for high-calorie, high-fructose-containing beverages? The investigators point out that the effects may be "more than strictly related to caffeine’s antioxidant behaviors." They cite a study in which rats receiving a high-fat diet given decaffeinated coffee had lower levels of hepatic fat and collagen, reduced liver oxidative stress (an effect of glutathione metabolism), and less liver inflammation -- emphasizing the likely importance of coffee itself, not caffeine, in preventing the progression of NASH. Potential beneficial components include aromatic extracts isolated from coffee beans and/or an elevation of glutathione levels or other antifibrogenic agents by coffee intake.^[7-9]

The Bottom Line

What advice can we offer to patients with fatty liver disease? Despite the preliminary results about the beneficial effects of vitamin E and omega-3 fatty acids, lifestyle changes (ie, weight loss through diet and exercise) are the only strategies proven to be effective.^[10,11] Moderate consumption of coffee may be a useful, benign adjunct -- but hold the cream and sugar!

References

1. Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DW, Harrison SA. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology. 2012;55:429-436.
2. Casiglia E, Spolaore P, Ginocchio G, Ambrosio G. Unexpected effects of coffee consumption on liver enzymes. Eur J Epidemiol. 1993;9:293-297.
3. Corrao G, Zambon A, Bagnardi V, D’Amicis A, Klastky A. Coffee, caffeine, and the risk of liver cirrhosis. Ann Epidemiol. 2001;11:458-465.
4. Ruhl E, Everhart J. Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States. Gastroenterology. 2005;128:24-32.
5. Modi A, Feldman J, Park Y, et al.. Increased coffee consumption is associated with reduced hepatic fibrosis. Hepatology. 2010;51:201-209.
6. Freedman N, Everhart J, Lindsay K, et al. Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C. Hepatology. 2009;50:1360-1369.
7. Lee K, Mitchell A, Shibamoto T. Antioxidative activities of aroma extracts isolated from natural plants. BioFactors. 2000;13:173-178.
8. Huber W, Scharf G, Rossmanith W, et al. The coffee components kahweol and cafestol inducegamma-glutamylcysteine synthetase, the rate limiting enzyme of chemoprotective glutathione synthesis, in several organs of the rat. Arch Toxicol. 2002;75:685-694.
9. Scharf G, Prustomersky, Huber W. Elevation of glutathione levels by coffee components and its potential mechanisms. Adv Exp Med Biol. 2001;500:535-539.
10. Sanyal A, Chalasani N, Kowdley K, et al. Pioglitizone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675-1685.
11. Centis E, Marzocchi R, Di Domizio S, Ciaravella MF, Marchesini G. The effect of lifestyle changes in non-alcoholic fatty liver disease. Dig Dis. 2010;28:267-273.

Source

The HCV Rooster Has Come Home to Roost

Written by Jose M Zuniga, Other, 09:50AM Feb 29, 2012

I wrote in a previous AIDScan blog about how hepatitis C virus (HCV) infection was expected to become a much larger public health problem as "baby boomers" begin to succumb to the disease. That prediction was borne out this week as research published in the Annals of Internal Medicine announced that HCV-related deaths in the United States now exceed HIV-related deaths, with an upward trend in HCV-related mortality, much of it attributed to individuals aged 45 to 64 years.¹ Equally alarming are data from a separate study also published in the Annals of Internal Medicine revealing that the majority of HCV infections in the United States are undiagnosed.²

These two papers reinforce the need to fully implement the US Department of Health and Human Services' "Action Plan for Prevention, Care, and Treatment of Viral Hepatitis," which calls for, among other things, an increase in targeted HCV screening of individuals born between 1945 and 1965.³ As the authors of the latter paper conclude, birth-cohort screening linked to HCV treatment with pegylated-interferon (PEG-IFN) and ribavirin (RBV) - which, incidentally, has been replaced with an even more therapeutically effective standard of care (see next paragraph) - might help significantly reduce HCV-related deaths versus current risk-based screening.²

In relation to HCV treatment, a new class of protease inhibitors - direct-acting antivirals (DAAs)-prescribed in combination with PEG-IFN and RBV, continues to demonstrate impressive cure rates. The HCV pipeline seems equally robust, with several more treatment options on the horizon, including potentially IFN-sparing options that will simplify dosing and address side effect concerns.

The bottlenecks to expanding access to HCV treatment, however, include both gaps in screening and diagnosis capacity, and in the numbers of clinicians able to prescribe the new standard of care for HCV infection. This, too, requires our immediate attention as well as a common understanding across medical disciplines, professions, and specialties that the needs of HCV-positive individuals require collaboration at practitioner-, clinic-, and health system-levels.

SHAMELESS PLUG WARNING: All of the issues discussed above will be addressed at the 2nd International Conference on Viral Hepatitis, March 26-27, 2012, at the New York Academy of Medicine in New York City. Visit www.iapac.org to view the program, faculty roster, and/or to register online.

1. Ly KN, Xing J, Klevens M, et al. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med. 2012;156:271-278.
2. Rein DB, Smith BD, Wittenborn JS, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med. 2012;156:263-260.
3. DHHS. Combating the Silent Epidemic of Viral Hepatitis: Action Plan for the Prevention, Care, and Treatment of Viral Hepatitis. 2011, US Department of Health and Human Services, Washington, DC, USA.

Source

FDA: New Risks for Statins With HIV/HCV Protease Inhibitors

Robert Lowes

Posted: 03/01/2012

March 1, 2012 — The US Food and Drug Administration (FDA) today announced that it is revising the labels of certain statins as well as protease inhibitors for HIV and hepatitis C virus (HCV) to warn about interactions between the 2 sets of drugs that could increase the risk for myopathy and kidney failure.

When taken together with the affected statins, HIV and HCV protease inhibitors can boost the blood level of the statins, which in turn can lead to myopathy. One of the most serious forms of myopathy is rhabdomyolysis, which can damage the kidneys, possibly resulting in kidney failure and death.

On Tuesday, the FDA announced that it was revising the labels of all statins to warn that they can raise blood glucose and hemoglobin A1c levels. The agency added that it was also updating the label of lovastatin to warn that a number of interacting drugs, including protease inhibitors, can increase statin exposure up to 20-fold and trigger rhabdomyolysis. The revised label for lovastatin will include new contraindications and dose limitations.

Today's FDA announcement lists lovastatin, simvastatin, atorvastatin, and rosuvastatin as statins that will undergo label changes to reflect the risk for interactions with HIV and HCV protease inhibitors. These statins will be contraindicated, cautioned against, or subject to dose limitations, depending on the exact combination of statin and protease inhibitor.

More information about today's announcement is available on the FDA's Web site.

To report adverse events related to the combination of statins and protease inhibitors, contact MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm, or by mail to MedWatch, FDA, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

Source

Also See:

1. FDA Hepatitis Update - Important info about interactions between certain hepatitis C drugs and cholesterol-lowering statin drugs
2. Statins and HIV or Hepatitis C Drugs: Drug Safety Communication - Interaction Increases Risk of Muscle Injury

FDA Hepatitis Update - Important info about interactions between certain hepatitis C drugs and cholesterol-lowering statin drugs

You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.

Please do not reply to this message.

The U.S. Food and Drug Administration (FDA) is issuing updated recommendations concerning drug-drug interactions between drugs for human immunodeficiency virus (HIV) or hepatitis C virus (HCV) known as protease inhibitors and certain cholesterol-lowering drugs known as statins. Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal.

Facts about statins and protease inhibitors

• Statins are a class of prescription drugs used together with diet and exercise to reduce blood levels of low-density lipoprotein (LDL) cholesterol (“bad cholesterol”).
• HIV protease inhibitors are a class of prescription anti-viral drugs used to treat HIV.
• HCV protease inhibitors are a class of prescription anti-viral drugs used to treat hepatitis C infection.
• A side effect of taking HIV protease inhibitors is increased cholesterol and triglyceride (fat) levels. Therefore, some patients taking HIV protease inhibitors may need to take cholesterol-lowering medicines such as statins.

The labels for both the HIV protease inhibitors and the affected statins have been updated to contain consistent information about the drug-drug interactions. These labels also have been updated to include dosing recommendations for those statins that may safely be co-administered with HIV or HCV protease inhibitors (see Statin Dose Limitations below).

Healthcare professionals should refer to the current drug labels for protease inhibitors and statins for the latest recommendations on prescribing these drugs.

Patients should contact their healthcare professional if they have any questions or concerns about taking protease inhibitors and statins.

Additional Information for Patients

• Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) protease inhibitors can interact with cholesterol-lowering statins to increase the risk of muscle injury.
• Patients should inform their healthcare professional about all medicines that they are taking or plan to take prior to starting an HIV or HCV protease inhibitor or statin.
• HIV and HCV protease inhibitors should never be taken (are contraindicated) with lovastatin (Mevacor) and simvastatin (Zocor) (see Statin Dose Limitations below).
• Patients should contact their healthcare professional if they have any questions or concerns about HIV or HCV protease inhibitors or statins.
• Patients should report side effects from the use of HIV or HCV protease inhibitors and/or statins to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of the page.

Additional Information for Healthcare Professionals

• Co-administration of human immunodeficiency virus (HIV) or hepatitis C virus (HCV) protease inhibitors with certain statins can increase the risk of myopathy/rhabdomyolysis.
• Healthcare professionals should follow the recommendations in the drug labels when prescribing HIV or HCV protease inhibitors with statins (also see Statin Dose Limitations below).
• Healthcare professionals should report adverse events involving HIV or HCV protease inhibitors and/or statins to the FDA MedWatch program using the information in the "Contact FDA" box at the bottom of this page.

Data Summary

Atorvastatin

The results from a drug-drug interaction study with atorvastatin and lopinavir/ritonavir that were previously in the atorvastatin label have not yet been validated. Therefore, these results have been removed from the label and the dose cap of atorvastatin 20 mg when co-administered with lopinavir/ritonavir has also been removed. Pending validation of the study, healthcare professionals should use caution when co-administering atorvastatin with lopinavir/ritonavir and use the lowest necessary dose of atorvastatin.

Lovastatin and simvastatin

Lovastatin and simvastatin are sensitive in vivo cytochrome P450 3A4 (CYP3A4) substrates. Therefore, strong CYP3A4 inhibitors are predicted to significantly increase lovastatin and simvastatin exposures. A literature review indicates that itraconazole, a strong CYP3A4 inhibitor, increases lovastatin exposure up to 20-fold, and the drug interaction appears to result in rhabdomyolysis.¹ Itraconazole increases simvastatin exposure up to 13-fold. Hence, other CYP3A4 inhibitors, including ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, nefazodone, human immunodeficiency virus (HIV) protease inhibitors, and the hepatitis C virus (HCV) protease inhibitors boceprevir and telaprevir, are also expected to significantly increase lovastatin and simvastatin exposures. Therefore, concomitant administration of lovastatin and simvastatin with HIV protease inhibitors or HCV protease inhibitors (boceprevir and telaprevir) is contraindicated.

Rosuvastatin

The HIV protease inhibitor combinations lopinavir/ritonavir and atazanavir/ritonavir increase rosuvastatin exposure up to 3-fold. For these combinations, the dose of rosuvastatin should be limited to 10 mg.

Reference

1. Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med. 1995;333:664-5.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Source: Email from FDA

Hypoferremia Predicts Treatment Response to IFN-α

Last Updated: March 01, 2012

THURSDAY, March 1 (HealthDay News) -- For patients with hepatitis C virus (HCV), hepcidin, a regulator of iron homeostasis, is induced following a single dose of pegylated interferon-α (PEG-IFNα), and may be a surrogate marker of immediate efficacy of IFN-α, according to a study published online Feb. 15 in Hepatology.

John D. Ryan, M.D., of the Mater Misericordiae University Hospital in Dublin, and associates analyzed blood samples of HCV patients to assess the clinical importance of the changes in iron homeostasis during the first 24 hours of treatment with PEG-IFNα.

The researchers found that a single dose of PEG-IFNα triggered a significant increase in serum hepcidin that peaked at 12 hours. This coincided with a 50 percent drop in serum iron and transferrin saturation over 24 hours. Significantly lower levels of serum iron and transferring saturation were seen at 12 and 24 hours in patients with a ≥2 log decrease in HCV viral load over the first 24 hours. Serum iron levels at 24 hours were an independent predictor of immediate HCV viral decline. Direct induction of hepcidin by IFN-α was seen in cell culture, and was controlled by the STAT3 transcription factor.

"Hepcidin induction occurs following the initiation of PEG-IFNα treatment for HCV, and is mediated via STAT3 signaling," the authors write. "The subsequent hypoferremia was greatest in those with the most significant decline in viral load, identifying systemic iron withdrawal as a marker of immediate IFN-α efficacy in HCV patients."

Abstract
Full Text (subscription or payment may be required)

Source

Statins and HIV or Hepatitis C Drugs: Drug Safety Communication - Interaction Increases Risk of Muscle Injury

AUDIENCE: Infectious Disease, Family Practice, Patients

ISSUE: FDA notified healthcare professionals of updates to the prescribing information concerning interactions between protease inhibitors and certain statin drugs. Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal.

BACKGROUND: Statins are a class of prescription drugs used together with diet and exercise to reduce blood levels of low-density lipoprotein (LDL) cholesterol (“bad cholesterol”). HIV protease inhibitors are a class of prescription anti-viral drugs used to treat HIV. HCV protease inhibitors are a class of prescription anti-viral drugs used to treat hepatitis C infection.

RECOMMENDATION: Healthcare professionals should follow the recommendations in the prescribing information ( drug labels ) when prescribing HIV or HCV protease inhibitors with statins. See the FDA Drug Safety Communication for additional information, including a data summary.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online: www.fda.gov/MedWatch/report.htm
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

Read the MedWatch safety alert, including a link to the FDA Drug Safety Communication, at:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm294294.htm

Source: Email Alert from the FDA

TMC435HPC2002 - Phase II Trial of TMC435 in Combination With PSI-7977 in Prior G1 Null Responders to Peg-IFN/RBV, Hepatitis C-Infected Patients

Provided by NATAP

This study is currently recruiting participants.

Verified February 2012 by Tibotec Pharmaceuticals, Ireland

http://clinicaltrials.gov/ct2/show/NCT01466790?term=hepatitis+C+AND+TMC+435&rank=1

TMC435+PSI-7977 with & without ribavirin for either 12 or 24 weeks total duration of therapy

This is a randomized (study drug assigned by chance), open-label ( patients and physicians know the names of the drugs they are taking), Phase IIa trial with TMC435 and PSI-7977 with or without ribavirin (RBV) in patients who are infected with chronic genotype 1 hepatitis C and who have failed standard treatment with pegylated interferon (PegIFN) and ribavirin (RBV).

The study will investigate the efficacy and safety of four different regimens: two arms will receive 12 weeks of treatment and two arms will receive 24 weeks of treatment. A target of 90 subjects will be randomly assigned to 4 treatment arms in the first study cohort (Cohort 1), which includes patients with lower stages of liver fibrosis (Metavir F0, F1, and F2). The trial will consist of a screening period of maximum 6 weeks, a 12-week or 24-week treatment period and a follow-up period.

Once treatment results are available on all patients in Cohort 1, the second cohort (Cohort 2) will begin enrollment in the study. A target of 90 patients will be enrolled in Cohort 2. Enrollment criteria will be the same as for Cohort 1, except that only patients with more advanced liver fibrosis (Metavir stage F3 or F4), will be enrolled. The treatment arms to be included in Cohort 2 will be determined by the results from the data analysis in Cohort 1.

Artificial liver cells win their creator prize for their potential to reduce animal experiments

Top images diseased liver cells, bottom images healthy liver cells. Credit: Tamir-Rashid

February 29, 2012

Cambridge research that created liver cells from stem cells has today been recognised with a national prize by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs).

Producing liver cells that demonstrate inherited liver diseases from human skin cells has earned Dr. Ludovic Vallier from the University of Cambridge a major prize from the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). These cells, known as human induced pluripotent stem cells (hIPSCs), have already attracted attention for the possibilities they offer to regenerate damaged tissues and organs. But it is their potential to reduce the number of animals used for screening potential drug treatments that led to Dr. Vallier receiving the Centre’s 3Rs prize for 2011.

The prize, sponsored by GlaxoSmithKline, of a £2,000 personal award and a £18,000 research grant, is for the scientific paper published in the last three years that contributes most to the advancement of the 3Rs (Replacement, Reduction and Refinement). Dr Vallier’s winning paper was published in The Journal of Clinical Investigation in 2010. He received his prize from Professor Paul Matthews OBE of GlaxoSmithKline at the NC3Rs Annual Science Review Meeting in London on 28 February.

Human liver cells (hepatocytes) cannot be grown in the laboratory and differences between rodents and humans mean that it is rarely possible to recreate the human disease completely in mice or rats or to use cultures of rat or mouse liver cells. Dr Vallier’s team took skin cells (dermal fibroblasts) from seven patients with a variety of inherited liver diseases and three healthy individuals (the controls). They then reprogrammed cells from the skin samples back into stem cells. These stem cells were then used to generate liver cells which mimicked a broad range of liver diseases – and to create ‘healthy’ liver cells from the control group.

These hIPSC-generated liver cells can provide in vitro models for basic research and drug discovery. Their use has already reduced the use of animals needed for the production of liver cells in the laboratories that have adopted this technology. The cells could also transform the investigation of chemical/drug-induced liver injury, a major concern for the chemical and pharmaceutical industries, by reducing dependence on animal testing.

Sharmila Nebhrajani, chief executive of the Association of Medical Research Charities (AMRC) said: “Charities invest over £1bn in health research each year, money raised by patients, their families and carers to understand the causes of disease and search for possible cures. Using 3Rs techniques, these prize winning researchers are bringing real hope to people with liver disease. What’s more – they are developing new methods for medical research which should benefit patients with all kinds of conditions.”

On presenting Dr. Vallier with his prize, Professor Paul Matthews, Vice-President for Imaging at GlaxoSmithKline, commented: “Ludovic Vallier’s innovative study describes the development and validation of a method to produce cells similar to those in a human liver. Such cells could replace animals for some types of early drug testing and could also help us to predict adverse clinical reactions. Using these cells for drug testing could be transformative. Ludovic and his colleagues have well illustrated how addressing the 3Rs converges with improving the quality of science!”

Provided by University of Cambridge (news : web)

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Cirrhotic patients experience increased daytime sleepiness from higher ammonia levels

Public release date: 1-Mar-2012

Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell

Hyperammonaemia reduces restorative sleep for patients with cirrhosis

Italian and Swiss researchers confirm that induced hyperammonaemia significantly increases daytime sleepiness in patients with cirrhosis. The findings available in the March issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases, show that higher blood levels of ammonia reduced the ability of cirrhotic patients to produce restorative sleep.

Chronic liver disease can lead to cirrhosis—a condition where scar tissue replaces healthy tissue, resulting in decreased blood flow through the liver and reduced liver function. Viral hepatitis, heavy alcohol use and obesity are among the causes of cirrhosis according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

In patients with chronic liver failure neuropsychiatric abnormalities may arise—termed hepatic encephalopathy (HE)—which experts believe to be due to neurotoxic substances that originate in the gut and are not cleared by the liver, such as ammonia. HE is common following a gastrointestinal bleed, which can be simulated by the oral administration of a mixture of protein mimicking that contained in blood ('amino acid challenge'; AAC).

To investigate the effects of excess ammonia and HE on sleep-wake patterns in patients with cirrhosis, Dr. Sara Montagnese and colleagues from the Dipartimento di Medicina in Padova, Italy and the Institute of Pharmacology and Toxicology in Zurich, Switzerland, induced hyperammonaemia in participants by an AAC. Ten cirrhotic patients and ten healthy controls underwent eight days of sleep quality monitoring, neuropsychiatric/wake and sleep EEG assessment prior to and following the AAC, and hourly ammonia and sleepiness assessments for eight hours post-AAC.

"Our study found that induced hyperammonaemia led to a significant increase in daytime sleepiness in both patients and healthy volunteers," said Dr. Montagnese. The authors also report changes to the EEG architecture of a sleep episode (nap) in patients with cirrhosis, which they believe points to a reduced ability to produce restorative sleep.

Dr. Montagnese concludes, "Our findings have important clinical implications in that subjective sleepiness may be used as a surrogate marker for HE." The authors also suggest that strategies aimed at reducing daytime sleepiness may result in improved sleep at night.

###

This study is published in Hepatology. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.

Full Citation: "Induced Hyperammonaemia may Compromise the Ability to Generate Restful Sleep in Patients with Cirrhosis." A Bersagliere, ID Raduazzo, M Nardi, S Schiff, A Gatta, P Amodio, P Achermann and S Montagnese. Hepatology; January 19, 2012 (DOI: 10.1002/hep.24741); Print Issue Date: March 2012. http://onlinelibrary.wiley.com/doi/10.1002/hep.24741/abstract.

Author Contact: To arrange an interview with Dr. Montagnese, please contact her directly at sara.montagnese@unipd.it or +39 049 8218675 begin_of_the_skype_highlighting +39 049 8218675 end_of_the_skype_highlighting.

About the Journal

Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Hepatology's current impact factor is 10.885.Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350.

About Wiley-Blackwell

Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit www.wileyblackwell.com or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

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Sequana Medical's ALFApump® System Receives Reimbursement in Germany for Breakthrough Technology in Ascites Management

ZÜRICH, March 1, 2012 /PRNewswire/ --

NUB Grants Approval for Fifteen Leading Hepatology Centres in Germany.

Sequana Medical announced today that its ALFApump® System has received German Neue Untersuchungs und Behandlungsmethode (NUB) approval which allows participating hospitals to receive reimbursement for innovative new products. Sequana Medical's ALFApump System is a fully implantable pump system designed to remove excess abdominal fluid, known as ascites, that collects in patients suffering from liver cirrhosis.

"This year only 16% of products submitted to the NUB received approval. Selection of the ALFApump System emphasizes the unmet medical need that exists in the management of refractory ascites and validates the ALFApump System as a breakthrough technology in ascites management" said Dr. Noel Johnson, President and CEO of Sequana Medical.

The ALFApump System consists of a subcutaneously implanted battery-powered pump connected to a catheter placed in the abdominal cavity which automatically and continually collects ascites as it forms and moves it into the bladder, where it is eliminated from the patient through normal urination. "This innovative development marks the beginning of a completely new treatment option for cirrhosis patients suffering with refractory ascites", says Professor Frank Lammert, Director, Department of Internal Medicine II, Saarland University Hospital, Homburg. Refractory ascites affects over 100,000 patients in Europe and the US every year and the number of patients is growing at an annual rate of 10% due to the accelerating incidence of hepatitis and obesity-related liver disease.

Ascites is a common complication among patients with late-stage liver disease and is the leading reason for hospitalization among patients with cirrhosis. Paracentesis, which involves inserting a large-bore needle into the abdomen to drain 5-10 liters of accumulated ascites, is the most common procedure for the treatment of ascites. However, paracentesis has to be repeated frequently, often every 7-10 days, as it doesn't prevent the re-accumulation of ascites. This repeated procedure is burdensome both to the patient and healthcare service provider.

"The economic benefits of the ALFApump System are substantial", says Dr. Johnson. "Use of the ALFApump System will provide considerable savings to payers by significantly reducing the requirement for paracentesis and avoiding repeated hospitalization." The NHS National Innovation Centre in the UK recently estimated that the ALFApump System could save the NHS £50 million per year. "Furthermore, the availability of this breakthrough technology to German hospitals will help to significantly improve the Quality of Life of patients suffering from refractory ascites. The successful NUB application for the ALFApump is a major milestone for Sequana Medical," concludes Johnson.

The ALFApump System was granted CE Mark in July 2011 and is currently being introduced into leading hepatology centres across Europe by Sequana Medical.

About Sequana Medical:

Founded in 2006, Sequana Medical is a Swiss medical device company backed by NeoMed Managment, VI Partners, Biomed Invest, Capricorn and Entrepreneurs Fund, dedicated to improving patient lives through innovative technologies to manage fluid overload in patients suffering from liver disease, cancer and congestive heart failure.

Sequana Medical
Emily Woodward, Product Marketing Manager
E-Mail: Emily.Woodward@sequanamedical.com
Tel: +41-44-446-50-74
Internet: http://www.sequanamedical.com

SOURCE Sequana Medical AG

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Old Drug Reveals New Tricks: How Interferon Works to Suppress Virus in Patients With HIV, Hepatitis

ScienceDaily (Feb. 29, 2012) — A drug once taken by people with HIV/AIDS but long ago shelved after newer, modern antiretroviral therapies became available has now shed light on how the human body uses its natural immunity to fight the virus -- work that could help uncover new targets for drugs.

In an article published online this month by the journal PNAS, a group of U.S. and Swiss researchers led by scientists at the University of California, San Francisco (UCSF) presented the first clinical assessment of how this drug fights infections in people. The drug, called interferon, is a biotechnology product based on a protein the body naturally produces to fight infections.

While purified interferon was given to people with HIV/AIDS in the early days of the epidemic because it alleviated many of the symptoms of the disease, its mode of action was always something of a black box.

"Nobody knew how it worked," said Satish K. Pillai, PhD, lead investigator and assistant professor of Medicine at UCSF and the San Francisco VA Medical Center.

Experiments in the laboratory in recent years have shown how interferon may work to suppress HIV in vitro, but there was no clinical evidence until now showing how the drug attacks HIV in treated patients. The problem is that so few people actually take interferon for HIV any more. However, interferon is still used in combination with other drugs to treat hepatitis C, which gave the team the possibility to assess its effect on HIV.

Interferon is commonly used to treat people with hepatitis C virus, and Pillai and his colleagues were able to identify 20 people enrolled in the Swiss HIV Cohort Study, which began in 1988, who have both HIV and hepatitis C. All 20 were taking interferon to treat their hepatitis C, but none were receiving antiretroviral drugs to treat HIV. This allowed researchers to examine how interferon works to suppress the virus.

How Interferon Works

The new work sheds further light on somewhat mysterious components of the immune system known as restriction factors, which are chemicals the human body produces to keep viruses like HIV in check and prevent them from infecting other cells.

These are just two fronts in the overall battle between HIV and the immune system -- a battle in which the immune system seeks to destroy the virus while the virus constantly counters by undermining the immune system.

Unlike other parts of the immune system, where whole cells gobble up invading pathogens or attack other cells, the action of these restriction factors is more subtle and localized within the infected cell itself -- one of the reasons scientists didn't appreciate what they do until just a few years ago.

One of them, called APOBEC3, fights viruses by stealthily jumping onto new virus particles as they form. Therein, the APOBEC3 protein fouls up HIV's genetic material by mutating it. When the virus tries to infect another cell, it no longer has the potency to replicate.

Another factor, called tetherin, takes an even more direct approach. It attaches to virus particles as they emerge from infected cells in the body and literally tethers them in place, preventing them from moving elsewhere in the body where they could infect new cells.

HIV has its own countermeasures to thwart these defenses. It produces a protein known as Vpu that neutralizes tetherin. Another HIV protein, called Vif, subverts APOBEC.

In the new study, Pillai and his colleagues showed that interferon combats HIV by mediating the action of both of these restriction factors. They collected samples from the 20 patients and measured the levels of APOBEC3 and tetherin before, during and after they took the drug interferon. The levels increased in response to interferon when the drug was in the bloodstream, and patients with the highest restriction factor levels showed the most precipitous drop in HIV viral load during interferon treatment.

While this insight does not immediately suggest new drugs or new ways of treating people with HIV, Pillai said scientists armed with this knowledge may one day figure out how to enhance this defense mechanism and specifically enhance the expression of restriction factors like tetherin and APOBEC3 in HIV-1-infected individuals.

If these factors can be induced to higher levels, their attack on the virus may become more potent -- perhaps even overriding HIV's countermeasures and helping flush the virus from infected cells.

The article, "Role of retroviral restriction factors in the interferon-α-mediated suppression of HIV-1 in vivo," was written by Satish K. Pillai, Mohamed Abdel-Mohsen, John Guatelli, Mark Skasko, Alexander Monto, Katsuya Fujimoto, Steven Yukl, Warner C. Greene, Helen Kovari, Andri Rauch, Jacques Fellay, Manuel Battegay, Bernard Hirschel, Andrea Witteck, Enos Bernasconi, Bruno Ledergerber, Huldrych F. Günthard, Joseph K. Wong, and the Swiss HIV Cohort Study.

In addition to UCSF, the authors of this study are affiliated with the San Francisco VA Medical Center, the Veterans Affairs San Diego Healthcare System at the University of California at San Diego, the Gladstone Institute of Virology and Immunology, and the Swiss university hospitals of Zurich, Berne, Lausanne, Basel, Geneva, St. Gallen and Lugano.

This work was funded by the National Institutes of Health and through the American Recovery and Reinvestment Act (ARRA). Additional support was provided by Swiss HIV Cohort Study Project 594; the Veterans Affairs Merit Review; and several Swiss National Science Foundation Grants. The Swiss HIV Cohort Study is supported by the Swiss National Science Foundation and the Swiss HIV Cohort Study Research Foundation.

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Differences in virological response to peginterferon-[alpha] plus ribavirin in HIV-positive patients coinfected with HCV subtypes 1a or 1b

JAIDS Journal of Acquired Immune Deficiency Syndromes:

POST ACCEPTANCE, 22 February 2012

doi: 10.1097/QAI.0b013e31824f5506

Original Article: PDF Only

Rallón, Norma I.; Pineda, Juan A.; Soriano, Vincent; Neukam, Karin; Vispo, Eugenia; Rivero, Antonio; Labarga, Pablo; Caruz, Antonio; Restrepo, Clara; Camacho, Angela; Barreiro, Pablo; Benito, Jose M.

Abstract

Background: Both viral and host factors influence response to peginterferon-[alpha] plus ribavirin (pegIFN[alpha]/RBV) in patients with chronic hepatitis C. The impact of these variables is more pronounced in HIV/HCV-coinfected individuals, in whom treatment response rates are lower.

Methods: Virological responses at multiple time points were assessed in all HIV/HCV-coinfected patients that completed a first course of pegIFN[alpha]/RBV. Viral responses were stratified by HCV geno/subtypes and IL28B rs12979860 variants.

Results: A total of 331 HIV/HCV-coinfected patients were analyzed. HCV geno/subtype distribution was as follows: HCV-1a in 97, HCV-1b in 62, HCV-3 in 122 and HCV-4 in 50. Age, gender, CD4 counts, plasma HIV-RNA and liver fibrosis stage did not differ significantly across HCV geno/subtypes. In contrast, mean serum HCV-RNA was greater in HCV-1a compared to the rest (p<0.0001). The proportion of IL28B CC variants was higher in HCV-3 compared to the rest (p=0.001).

Virological responses were better in HCV-1b than HCV-1a at any given time point during therapy. IL28B variants significantly influenced virological responses across all HCV-1 subtypes, with the strongest effect seen in HCV-1a. In a multivariate linear regression analysis, both HCV-1b and IL28B CC variants were significantly associated with greater HCV-RNA drops at weeks 4 (R=0.52, p<0.0001) and 12 (R=0.49, p<0.0001) of therapy.

Conclusion: The response to pegIFN[alpha]/RBV therapy is lower in HCV-1a than HCV-1b in HIV/HCV-coinfected patients. The strongest influence of IL28B variants is seen in HCV-1a. This information may be relevant when using most directly acting antivirals in coinfected patients along with pegIFN[alpha]/RBV, given that selection of drug resistance occurs more frequently in HCV-1a than HCV-1b.

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Hepatitis C vaccine signals landmark University of Alberta discovery

(Photo by Julianna Damer/The Gateway)

Last updated: February 29, 2012 5:23 pm

Vaccine could protect against all forms of virus

Andrew Jeffrey — The Gateway (University of Alberta)

EDMONTON (CUP) — A University of Alberta team has made a breakthrough in hepatitis C research, creating a vaccine that could potentially combat all forms of the liver-destroying virus.

The vaccine was developed by Michael Houghton, a U of A researcher who first discovered the hepatitis C virus (HCV) in 1989. The vaccine exposes the human body to a non-infectious sub-unit of the HCV so that it can begin developing antibodies to protect against the virus. These antibodies are able to cross-neutralize against the seven genotypes of the virus.

“Previously, many people believed that the virus was impossible to neutralize with just one type of vaccine because there are so many different genotypes,” explained John Law, a member of the U of A research team.

“This is a proof of principle finding — showing that we can make a vaccine that can allow cross protections of many different varieties of the hepatitis C virus.”

Houghton began developing a vaccine more than a decade ago, and was recruited by the U of A’s Li Ka Shing Institute of Virology three years ago to continue his research. Law attributes much of the success of their team to Houghton’s dedication.

“We didn’t really make anything special. Mostly it’s been the efforts of Dr. Houghton. We’ve persisted and been able to go through the hurdles of finally getting the samples, getting the trial, and eventually testing the results and being able to find out the answer,” Law said.

“He stayed with his idea and eventually carried it out to a point where now we can see there is a very good potential for things that are going to happen.”

Law said an obstacle in creating the vaccine is the HCV’s ability to mutate quickly and exists in a variety of genotypes, similar to AIDS.

Law predicts that it will still take another five to seven years before the vaccine is ready to be released. The research has only completed the first of three phases needed for the FDA to approve the vaccine. Although its safety has already been tested, the vaccine will require further testing in a clinical setting.

The vaccine has already been presented by the research team to various other members of the virology community.

Last weekend, the team travelled to Montreal to present their findings at a Canadian symposium for hepatitis C. Law is hopeful that the team can improve upon their vaccine further before releasing it to the public.

“We’re basically trying to understand those antibody responses, and trying to find out which part of the sub-unit the antibody recognizes. There might be some common area between the genotypes that the antibody can see that is therefore blocking infections of HCV,” Law explained.

“We can maybe learn the mechanism to increase the efficacy of the vaccine and be able to design a better vaccine and move forward.”

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Also See: The Scientist Who Discovered Hepatitis C Says He’s Now Discovered the Vaccine