Expanding Access to Treatment for Hepatitis C in Resource-Limited Settings: Lessons From HIV/AIDS

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from Jules: Screening projects are primary, they need to be comprehensive.

Clinical Infectious Diseases May 2012

Nathan Ford,1,2 Kasha Singh,4 Graham S Cooke,3,5 Edward J Mills,7 Tido von Schoen-Angerer,1 Adeeba Kamarulzaman,8
and Philipp du Cros6

1Me'decins Sans Frontie'res, Geneva, Switzerland; 2Centre for Infectious Disease Epidemiology and Research, University of Cape Town, and 3Africa
Centre for Health and Population Studies, University of KwaZulu-Natal, South Africa; 4Centre for Clinical Microbiology, University College London,
5Faculty of Medicine, Imperial College London, and 6Me'decins Sans Frontie'res, Manson Unit, London, United Kingdom; 7Faculty of Health Sciences,
University of Ottawa, Canada; and 8Department of Medicine, Center of Excellence for Research in AIDS, University of Malaya, Kuala Lumpur, Malaysia

Abstract

The need to improve access to care and treatment for chronic hepatitis C virus (HCV) infection in resource-limited settings is receiving increasing attention. Key priorities for scaling up HCV treatment and care include reducing the cost of current and future treatment; simplifying the package of care; identifying opportunities to shift specific tasks to nonspecialists to overcome human resource constraints; service integration with human immunodeficiency virus (HIV) clinics, prison health services, and needle syringe and oral substitution therapy programs; improving surveillance, monitoring, and research; encouraging patient and community engagement; focusing specifically on the needs of vulnerable groups; and increasing financial and political commitment. Many of these obstacles have been addressed in rolling out treatment for human immunodeficiency virus during the last decade, and a number of lessons can be drawn to help improve access to HCV care.

Hepatitis C virus (HCV) infection is a growing public health concern, with an estimated 170 million persons infected globally and 350 000 deaths each year due to hepatitis C-related liver disease [1]. In 2010 the World Health Assembly adopted a resolution promoting integrated and cost-effective approaches to the prevention, control, and management of viral hepatitis and noted in particular the need to address hepatitis in the context of the human immunodeficiency virus (HIV) epidemic [2]. A number of countries in resource-limited settings are providing treatment of HCV infection through dedicated services with reasonable success [3]. Generally, however, access to care remains limited, particularly in poorer regions such as India and sub-Saharan Africa [4].

Challenges to increasing access to treatment of HCV infection in resource-limited settings include the high cost and perceived complexity of treatment, side effects that hamper adherence, long treatment duration, and insufficient political commitment. Early efforts to increase access to antiretroviral therapy (ART) for HIV/AIDS in resource-limited settings were impeded by similar challenges. We reflect on the experience of scaling up access to ART during the last decade and draw lessons for improving access to treatment and care for persons with HCV.

A decade ago, treatment for persons living with HIV/AIDS was unavailable in most developing countries, and there was debate about whether treatment should be considered given the considerable challenges faced [5]. Yet despite these early concerns, >6.6 million persons are now receiving ART in the developing world [6]. Several critical issues had to be confronted before large-scale HIV treatment programs could be established. These are summarized in Table 1 and discussed below.

REDUCING THE COST OF TREATMENT

Until mid-2000, ART cost about US $10 000 per patient per year, and cost-effectiveness studies concluded that treatment should not be prioritized [7]. This equation shifted as generic competition drove down the cost of treatment. This was largely achieved thanks to significant political support by a global alliance of civil society groups, and in particular persons living with HIV/AIDS and health providers, nongovernmental organizations, and academics who worked together as a global coalition for the rights of those with HIV/AIDS to access treatment [5]. In 2001 a generics manufacturer announced that triple therapy could be manufactured for less than a dollar a day. This created a dynamic of global market competition that drove down the price of standard triple therapy from US $10 000 per patient per year to almost US $60. Today, >80% of ART used in low-income and middle-income countries is manufactured by Indian generics firms [8].

Treatment of HCV infection is currently expensive in developing countries. Generic forms of ribavirin are available, but pegylated interferon is patented in a number of low- and middle-income countries, and overall costs of treatment are high: a recent survey of 5 Asian countries reported that public sector prices for a 48-week course of combination therapy range from US $12 000 (Vietnam) to US $18 500 (Indonesia) [9]. Several alternative sources of pegylated interferon have recently been developed that have helped drive down the cost of treatment. In Egypt, for example, a locally manufactured biosimilar of pegylated interferon is produced [10], and market competition has supported a 6-fold reduction in the price of both originator and generic products: a 48-week treatment course of pegylated interferon and ribavirin currently costs less than US $2000 in Egypt. Although comparative safety and efficacy data are limited for generic pegylated interferon products, this nevertheless demonstrates that substantial price reductions are possible.

The World Health Organization (WHO) prequalification scheme has played a critical role in the availability of affordable antiretrovirals. This scheme is used by donors, implementing organizations and many national programs to assure the quality of generically produced antiretroviral drugs [11]. Similarly, quality assurance of antivirals for HCV would give confidence to donors, patients, and implementing organizations and would allow developing countries to fast-track registration of generic and biosimilar sources of antivirals for HCV. Existing biosimilars of pegylated interferon are registered in only a few countries and have not been quality assessed by WHO, although guidance for the evaluation of biosimilars has been published elsewhere [12].

Access to the newest generation of HCV medicines will be critical, because these drugs have the potential to significantly simplify treatment regimens and improve outcomes, offering particular advantages for use in settings with limited facilities [13, 14]. This will likely require concerted public and political mobilization to pressure originator companies to reduce prices and stimulate generic competition.

SIMPLIFYING THE MODEL OF CARE

HIV/AIDS care in developed countries is highly specialized. Treatment initiation decisions are informed by CD4 count and viral load, and treatment regimens are individualized according to genotypic resistance pattern, clinical response, side effects, and patient preference. More than 30 different antiretroviral drugs are currently approved, allowing for frequent medication adjustments.

In resource-limited settings, access to laboratory tests and choice of medication are limited. Guidelines for the management of HIV/AIDS in resource-limited settings developed by the WHO have helped to simplify management by specifying only a limited selection of once- or twice-daily regimens for first- and second-line therapy and recommending a limited set of laboratory tests that are desirable but not essential [15]. The development of antiretroviral agents as fixed-dose combination tablets has greatly helped to standardize and simplify patient care. In addition, low-technology innovative solutions to provision of essential tests have also been pursued, such as dried blood spots for viral load testing [16].

Similar simplification is required to support HCV management in poorly resourced settings. Current guidelines for treatment of HCV infection are from developed country tertiary care settings; include a variety of tests to initiate and guide care, such as regular viral load monitoring; and involve a range of antiviral and supplementary medications. Research to determine the need for each test will be important to make HCV treatment feasible and cost-effective in resource-limited settings.

Recent innovations enabling noninvasive assessment of liver fibrosis have important possible applications in HCV management decisions in resource-limited settings. These range from those employing the use of widely available blood tests, such as aspartate transaminase (AST) to platelet ratio (APRI) and potentially portable new technologies, such as transient elastography (eg, FibroScan) [17]. These tests generally perform well in distinguishing mild liver fibrosis from advanced fibrosis and cirrhosis, but clinical decisions for treatment often require the diagnosis of intermediate stages of fibrosis and this limits the usefulness of such tests [18]. Findings of a large European study suggest that the FibroScan technique might be more useful than blood markers [19]. Small, portable FibroScan units make the approach more feasible in resource-poor settings, but problems with unreliable readings in inexperienced hands and maintenance of equipment create significant challenges.

The necessity of other investigations in the treatment of HCV infection, in particular HCV viral load monitoring and genotype tests, is an important consideration in planning implementation of HCV treatment programs in resource-limited and isolated settings. Increasing access to viral load technology is becoming a priority within HIV/AIDS programs, and this could serve to benefit HCV programs [20]. Given the paucity of clinical findings in HCV infection before end-stage disease with hepatic decompensation, the availability of investigations may prove to be a larger hurdle for HCV programs than it has been in the case of HIV. Finally, the relative benefit of interleukin 28B testing, which is increasingly used to help predict treatment response in Western settings, needs careful consideration [21].

HCV program development can also learn from simplification approaches to scaling up treatment for multidrug-resistant tuberculosis. Multidrug-resistant tuberculosis care requires frequent injections, multiple medications, and long durations of treatment. Through models of care that provide psychosocial support and early recognition and management of adverse effects and through the decentralized provision of care, good programmatic outcomes have been achieved [22].

In the treatment of HIV infection, the introduction of less toxic drugs and simplified, fixed-dose combinations has been associated with improved adherence [23]. The arsenal of HCV drugs is rapidly changing, and with recent data on newer oral antiviral agents [24], interferon-free treatment for HCV now seems achievable, offering the possibility of injection-free treatment [25]. Mechanisms for accelerated access to simplified treatment of HCV infection should be prioritized.

The simplification agenda for HCV management will need to take into account the different capacities of different settings. Just as guidelines for ART specify a number of diagnostic tests that, although not essential, are nevertheless highly desirable [15], so recommendations for HCV management will need to strike a balance between what can be done today and what should be the standard for tomorrow.

TASK SHIFTING TO OVERCOME HUMAN RESOURCE SHORTAGES

In developed countries, HIV/AIDS has conventionally been managed by specialist physicians. However, health systems in resource-poor settings where the burden of HIV/AIDS is greatest face a critical shortage of the most basic essential health staff, with some high-burden countries having a 100-fold fewer doctors per population compared with the United Kingdom or United States [26]. To address this challenge, the WHO published guidelines for task shifting, outlining a range of tasks that could, with adequate training and supervision, be delegated to nonphysician clinicians [27]. Randomized trials and cohort studies have subsequently validated the safety and effectiveness of task shifting for the provision of ART [28].

The decentralization of HCV management to lower levels of the health system has been assessed in the United States as a way to improve access to care. Outcomes of HCV treatment provided at community settings with specialist supervision via videoconference were found to be comparable to care provided at a dedicated HCV clinic in a tertiary center [29]. This strategy will help to ensure that care is not limited by a lack of specialists and the need to travel to tertiary level centers. Operational research should be conducted to assess the potential for different models of patient support and define the appropriate skills mix for resource-limited settings.

SERVICE INTEGRATION

The provision of ART as a vertical (disease-specific) program was an important early starting point in the AIDS response, allowing for rapid establishment of services. As programs expanded, integration of HIV/AIDS services into the broader health system has become a priority [30]. Primary care services in general, and clinics for antenatal care, tuberculosis, and sexually transmitted infections in particular, have proved to be important entry points for the diagnosis and treatment of HIV, and integration of services has had an important influence on patient outcomes [31].

Similarly, for HCV services to reach larger numbers of persons in a sustainable way, efforts will need to be made to link HCV prevention and treatment services and integrate treatment and care with other health services in which persons at risk are likely to be identified and where provision of quality of care is possible: needle syringe and oral substitution therapy programs, HIV clinics, and prison health services. The first step would be to increase access to HCV diagnostics in such services.

Integration of HIV management into general health services has had mixed results, providing both positive and negative lessons for HCV care [32]. The resulting literature provides an important resource for HCV management programs. For example, a recent review of integration of HIV and tuberculosis highlights some of the ways in which vertical approaches have led to inefficient and ineffective programming for both diseases [33].

SURVEILLANCE, EVALUATION, AND RESEARCH

During the past decade, significant improvements in HIV disease surveillance have informed service provision and directed research. In contrast, there is a dearth of epidemiological information regarding HCV infection rates in most parts of the world [4]. Improved epidemiological information will be critical in expanding HCV services, and many of the approaches developed to collect information about HIV incidence and transmission could be adapted for use in HCV. Increased information regarding the global scale and burden of the epidemic in different settings will increase awareness of the epidemic. Increased testing for HCV infection will be an important component of accurate disease surveillance and is also critical to treatment and prevention efforts [34]. This is particularly important because the development of appropriate treatment strategies will require accurate information regarding genotype prevalence in different countries.

The use of simplified reporting systems with standardized indicators in ART programs has allowed regular monitoring and the strategic direction of resources to improve service provision through operational research [35]. In the development of treatment programs for HCV infection, building in methods of data collection and recording to allow regular and routine program review will help facilitate ongoing service feedback and improvement and will also help generate evidence around the relative benefits and cost-effectiveness of different program strategies.

The research and development agenda for HCV needs to take better account of the specificities of resource-limited countries. For HIV, factors such as heat stability of medications, minimal monitoring of drug regimens, and simplified drug dosing are important for simplifying care [36]. The consideration of such factors in the process of drug development for HCV could greatly facilitate the adoption of treatments in resource-constrained settings.

PATIENT AND COMMUNITY ENGAGEMENT

In the scale-up of treatment for HIV infection, lack of patient knowledge and stigma are understood to influence uptake of testing and adherence to treatment. Efforts to tackle HIV thus need to address both access to diagnosis and care, as well as community education and stigma reduction components [37]. Similarly, persons with HCV infection are often not aware of their diagnosis or lack access to information about the benefits of treatment [38-41]. Efforts to scale up HCV treatment must tackle community education and stigma issues, especially among intravenous drug users.

Initially, there was considerable concern about the challenge of achieving adequate adherence to ART in resource-limited settings, but reported rates of early adherence in sub-Saharan Africa were found to be better than in North America [42]. Adherence counseling by patient experts or community health workers has been demonstrated to be one of the most effective ways of supporting patient adherence [43], while at the same time relieving the burden on health workers. More recent reviews have documented substantial attrition between diagnosis and initiation of ART, highlighting the need to develop supportive models of care that start at the point of diagnosis [44].

The treatment of HCV infection, like ART for HIV infection, is associated with a range of adverse effects, many of which are nonsevere but can lead to poor treatment adherence. A recent meta-analysis of HCV program outcomes in low- and middle-income settings found relatively low rates of defaulting from care (4%) and low frequency of adverse events leading to treatment discontinuation (4%) [3]. Nevertheless, adherence support interventions for HCV treatment need to be better defined, particularly as a proportion of patients who will be eligible for treatment may be asymptomatic. Treatment literacy programs to increase patients' understanding of HCV disease and treatment, together with dedicated peer support to assist with adherence and social issues, will likely be an effective way to ensure that patients are supported during the course of their treatment. Community engagement in other areas of the care pathway such as testing and screening have proved effective in scaling up access to HIV care [45] and should also be explored for HCV.

The engagement of persons living with HIV has been acknowledged as one of the most important achievements in the AIDS response [46]. Persons living with HIV/AIDS have also played a critical political role through activism to pressure price reductions for antiretroviral drugs, increased funding, and acceleration of research and development [47]. Similar activism is beginning to take shape for HCV and will be critical to making treatment more widely available [48].

ADDRESSING THE NEEDS OF VULNERABLE GROUPS

From the outset, efforts to scale up ART in developing countries have included a specific focus on such populations who, because of oppression and vulnerability [49], have been systematically excluded from access to treatment and care. International reports mapping progress toward universal access to prevention and treatment dedicate specific sections to population groups, such as sex workers, injection drug users, men who have sex with men, and prisoners [50], and international funding mechanisms provide specific funding for programs addressing the needs of vulnerable groups.

Given the high burden of HCV infection among injection drug users [51], increased transmission risk in prisoners, and the substantial overlap between the HIV and HCV epidemics, national and international efforts to support improved access to HCV prevention, treatment, and care should benefit from the positive experiences of expanding ART to vulnerable groups.

FINANCIAL AND POLITICAL COMMITMENT

The dramatic reduction in the cost of treatment was essential to shifting the cost-effectiveness equation in favor of the widespread provision of ART. In addition to increased bilateral funding from a number of Western governments, several international funding streams were established to support ART scale-up, notably the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM), and the US President's Emergency Plan for AIDS Relief [52].

To support an international effort to increase access to treatment and care for HCV infection, dedicated funding will be required to support the expansion of access to diagnostics and treatment and the promotion of operational research to develop adapted models of care. The GFATM is already providing some, albeit limited, funding for HCV treatment for individuals coinfected with HCV and HIV, and other donors, such as UNITAID, should explore how they can support HCV care [53]. However, recent reductions in donor contributions to GFATM threaten to limit the number of programs that can be supported [54]. Political commitment from the national governments of countries most affected by HIV/AIDS has also been an essential driver of the global response to HIV and will be critical in enabling the provision of HCV treatment and care in institutions under the management of correctional services.

CONCLUSIONS

Expanding access to hepatitis treatment in resource-limited settings will require a dedicated effort to overcome practical and political challenges. This also applies to care and treatment for persons with hepatitis B virus infection [55], for which many of the lessons outlined in this article apply. Perhaps the most important lessons from the scaling up of ART during the last decade is that this will not happen without clear political commitment, and the engagement of civil society to hold policy makers and drug manufacturers to account. Recent demonstrations by activists in India to call for reduced drug prices for hepatitis treatment could be the first step toward reducing the present inequality where hepatitis treatment and care are, for the most part, available only to patients who are fortunate enough to live in the developed world.

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Turning Lymph Nodes Into Liver-Growing Factories

If your liver fails, having 40 small but functional livers scattered around your body might be the next best thing.

by Adam Piore

From the March 2012 issue; published online April 11, 2012

For people suffering from advanced liver disease, the prognosis is bleak. In many patients, such as those with cirrhosis, the liver becomes so clogged with scar tissue that healthy cells are choked off, preventing it from fulfilling its role of filtering toxins. The only cure is a liver transplant. Yet with just 6,000 available organs for some 100,000 patients each year, chances of winning the liver lottery are slim. And if you’re elderly or suffering from another disease, the chances are closer to zero.

But a surprising new technique under development by University of Pittsburgh stem cell researcher Eric Lagasse may radically improve those odds. Lagasse, based at Pitt’s McGowan Institute for Regenerative Medicine, has discovered how to turn any one of the body’s 500 lymph nodes—the small, oval-shaped organs where immune cells gather to fight invading pathogens—into an incubator that can grow an entirely new liver. Creating a whole set of miniature new livers might take as little as obtaining liver cells from healthy donors and placing them inside the lymph nodes of patients suffering from liver disease.

The concept was born in 2007, while Lagasse was pondering how to overcome a major roadblock to liver regeneration—in those with liver disease, the organ forms scar tissue that destroys its ability to heal. But then he noticed emerging evidence that transplanted liver cells could survive in unusual areas of the body, for instance under the renal capsule, a fibrous layer that protects the kidney from trauma. Lagasse reasoned that if he could implant liver cells away from the diseased organ, instead of succumbing they just might multiply and thrive.

So he set to work trying to grow liver cells outside the dying organ. As his test tube, he used mice with end-stage liver disease, implanting liver cells, or hepatocytes, from another mouse into their kidney capsules, under the skin, and into the spleen. Most of the mice died within eight weeks, the usual prognosis for end-stage liver failure in mice. But that changed when Lagasse injected cells into the belly: The mice gained weight, recovered energy, and within weeks appeared healthy.

After watching those mice thrive for several months, Lagasse repeated the experiment using fluorescent markers to trace the path of the liver cells. To his surprise, they had migrated to lymph nodes, where they grew to form large nodules that, in aggregate, reached a mass capable of keeping the animal alive.

It actually made sense. In many ways, lymph nodes are ideal bioreactors for growing new livers. They have an unusual capacity to expand, allowing them to accommodate an entire organ. They have ready access to the bloodstream, which nurtures new cells with nutrients as well as hormones and signaling agents needed for growth. And since the body has many lymph nodes, some can sacrifice their traditional duties to grow livers. The injections were so successful, Lagasse realized, because the belly provided enough space for cells to migrate.

Further experimentation showed Lagasse that if he injected hepatocytes directly into the lymph nodes, the cells picked up signaling proteins (essentially SOS signals to grow) released into the bloodstream from the dying liver. “There is communication between the new and a diseased liver,” Lagasse says. “They share some functions. We don’t totally understand the signaling mechanism, but we don’t need to if it works.”

Using his technique in mice, Lagasse has already succeeded in growing 20 to 40 small livers that gradually pick up the slack as the central liver fades. Together the mini-livers add up to 70 percent the size of a normal liver.

So far, Lagasse has not seen adverse reactions in his experimental mice. Rejection is not a problem because the animals were genetically engineered to share identical DNA, eliminating the risk that the immune system would attack foreign hepatocytes. In humans, Lagasse is banking on immunosuppressant drugs to prevent rejection. Further ahead, he is looking to an emerging technology known as induced pluripotent stem cells (iPSCs), in which adult cells are reprogrammed to be like embryonic stem cells so they can transform into any type of cell. Doctors could then collect blood or skin cells from a patient and turn them into healthy liver cells, enabling patients to be their own donors.

Even if rejection can be controlled, patients gravely ill from end-stage liver disease might succumb to surgery itself. To address this, Lagasse has injected hepatocytes into lymph nodes in peripheral parts of a mouse’s body—under the knee or arm—because that requires less invasive surgery. Growing a liver behind a knee is not ideal; in humans it might cause a bump weighing more than a pound in an inconvenient spot. But cultivating a liver in these peripheral areas could allow a very sick patient to survive long enough to recover the strength to undergo implantation in a more practical location.

Next Lagasse plans to replicate his experiments in pigs and hopes to implant human patients within the next few years. In principle, there’s no reason the approach should be limited to livers. “We’re talking about bioreactors that could grow any number of tissues inside the body,” Lagasse says. “This could work for any organ that secretes things or produces cells.” The thymus and pancreatic cells may be future candidates.

Stem cell expert Robert Lanza, who heads scientific research at Advanced Cell Technology in Massachusetts, calls the research an “exciting, novel idea.” But he sounds notes of caution. Liver cells carry out hundreds of different functions, only some of which Lagasse has tested in mice, and it is unlikely that transplanted cells could fulfill all of them in humans. “Also, you can envision all sorts of locations where it would not be good to have these cells,” he says. “What if they migrate to the lungs or brain?”

Lagasse concedes the many hurdles that lie ahead, not the least of which is convincing people that his bizarre transplantation technique might work. “This is such a wild idea, we need to demonstrate it could actually be used on a patient,” Lagasse says. “Still, I’ve spoken to many surgeons who are very excited about it.”

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GROWING A NEW YOU

Regenerative medicine is in its infancy, but researchers are on the cusp of regrowing all kinds of limbs and organs. The following are some of the most promising candidates.

Bladder Six years ago the bladder became the first partially lab-grown organ to be implanted in humans. A swab of a patient’s bladder cells were cultured in a dish, molded to the shape of the bladder, and tacked onto their original damaged organ, restoring function. In 2010 researchers grew bladders from scratch using baboons’ bone marrow stem cells.

Windpipe Last year doctors in Sweden successfully transplanted the first synthetic windpipe grown using a patient’s stem cells. Previous trachea transplants had relied on a donor organ.

Muscles and Digits In 2005 a man accidentally lopped off part of his finger. Following advice from his surgeon brother, he sprinkled the nub with powder containing part of a pig’s bladder known to contain powerful proteins that regenerate tissue. The finger regrew in four weeks. Tissue engineers at Pitt are using the technique to help others regrow muscle in damaged arms and legs.

Heart Fish and amphibians can produce new heart cells to repair damage, but mammals cannot. Researchers at the University of Washington and elsewhere are using stem cells to trigger the growth of these cells, which stop regenerating in mammals after birth. So far the technique has reduced scarring and improved cardiac function in rats following heart attacks.

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HCV Independently Raises Risk of Premature Death in AIDS Patients

From Reuters Health Information

By Megan Brooks

NEW YORK (Reuters Health) May 04 - Despite competing risks, chronic hepatitis C virus (HCV) infection is independently associated with a 50% increase in mortality among patients with a diagnosis of AIDS, new research suggests.

"Effective HCV treatment may benefit HIV/HCV co-infected patients with AIDS," according to a report online April 24 in Clinical Infectious Diseases by Dr. Andrea D. Branch at Mount Sinai School of Medicine in New York City and colleagues.

In the United States and Europe, about 30% of HIV-positive patients are also infected with HCV. A recent meta-analysis showed that the overall mortality risk ratio for HIV/HCV co-infected patients is increased by about 35%.

Yet, it's not clear, say the researchers, whether these results apply to patients with CDC-defined AIDS in the era of combination antiretroviral therapy, "because their mortality rate continues to be approximately five times higher than that of HIV-positive patients without a diagnosis of AIDS. Competing risk factors might eclipse the mortality risk of HCV infection in current patients with AIDS, just as they did in the early years of the epidemic."

Dr. Branch and colleagues tracked 2,025 patients with AIDS enrolled in the Longitudinal Studies of the Ocular Complications of AIDS (LSOCA) and followed prospectively for a median of over six years. LOSCA is one of only a few cohort studies limited to persons diagnosed with AIDS, but without further exclusion criteria. It focuses exclusively on the era following introduction of combination antiretroviral therapy.

An analysis of plasma banked at enrollment from all 2,025 patients revealed that 428 (21%) had evidence of past or current HCV infection. Nearly four-fifths (337, or 79%) were HCV RNA positive, indicating chronic HCV infection, and 91 (21%) had HCV antibodies but no HCV RNA, indicating past infection. The remaining 1,597 had no HCV markers.

Overall, 558 study subjects died during follow up. After adjusting for demographic factors and known risk factors for death, the relative risk of dying during follow-up was 1.5 (p=0.001) in patients with chronic HCV infection. In contrast, mortality was not increased in patients with past (cleared) infection (RR, 0.9; p=0.82). In patients with chronic HCV infection, 20.4% of deaths were liver-related vs 3.8% in patients without HCV infection.

Dr. Melanie Ott, senior investigator at the Gladstone Institutes in San Francisco, California, who was not involved in the study, told Reuters Health that a 1.5-fold increase in mortality is "not earth-shattering in AIDS patients with chronic HCV coinfection."

Nor is it surprising, she said, that the mortality due to liver-related diseases is increased in these patients. "It is actually surprising that 'only' approximately 20% of death in these patients is liver-related given the fact that HIV coinfection worsens the outcome of HCV infection."

Dr. Ott also said the finding that liver-related but not overall mortality is also elevated in HIV patients who cleared HCV suggests that "transient contact with HCV could prime the liver for fatal liver damage on the background of HIV infection."

Dr. Branch and colleagues add, "The negative impact of liver disease on survival emphasizes the need for patients with AIDS to be aware of their HCV status so that they can fully participate in their health care and risk reduction."

They also found that 100 (30%) of 337 subjects with chronic HCV infection said that they had never been given a diagnosis of this disease.

"Heightened HCV awareness" may increase the proportion of patients seeking treatment and achieving sustained virological response (SVR), Dr. Branch and colleagues say.

They point out that while current anti-HCV treatments produce a sustained viral response (SVR) in only 25% to 50% of HIV/HCV co-infected patients, "SVR rates are expected to rise soon as (direct) acting antiviral drugs for HCV enter the clinic."

Even so, "optimizing treatment and managing drug-drug interactions will be significant challenges in the years ahead," the authors conclude.

The study was supported by grants from the National Institutes of Health Eye Institute to the Mount Sinai School of Medicine; the Johns Hopkins University Bloomberg School of Public Health and the University of Wisconsin; and by grants from the National Institute of Drug Addiction and the National Institute of Digestive Diseases and Kidney Disease to the Mount Sinai School of Medicine. One author has relevant financial disclosures, all listed with the original article.

SOURCE: http://bit.ly/IGGqlK

Clin Infect Dis 2012.

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Text message prompts ‘improve medicines adherence’

Published on 26/04/12 at 08:00am

Patients with long-term diseases benefit from having text message reminders to take their medication.

This is according to a new review, published this week in the Journal of the American Medical Information Association.

It said that electronic reminders such as text messages help patients with chronic conditions take their medication regularly - but warned it only had data for the short-term. Longer-term studies would need to be conducted to review its efficacy over greater periods of time, the authors said.

A key issue for people living with long-term conditions is their ability to stick to their drug schedule, and numerous attempts have been made to come up with an effective solution.

One of the most common reasons patients give for not taking their medicines is that they simply forgot, say the authors.

The review looked at 13 studies, involving patients with HIV infection, high blood pressure, asthma, glaucoma, and those taking the contraceptive pill.

Four studies reported on text messages (SMS); seven on audiovisual reminders provided by hand held devices; and two on pager services.

In all, nine of the studies showed that electronic reminders boosted patients’ ability to stick to their drug dosing schedules. Text messages in particular, but also audiovisual prompts, seemed to get the best results.

Ten of the studies monitored the impact of these reminders on patients for less than six months, and only one of the three studies monitoring patients for longer than this reported a significant impact on adherence rates.

The review’s authors said: “Patients who are adherent at first can become non-adherent over time,” adding that: “automated reminders can become a routine, resulting in habituation.”

Nevertheless, they conclude their findings indicate that electronic reminders do seem to be helpful for patients with long-term conditions in the short-term, and that this approach is both easy for healthcare professionals and patients to adopt.

“Reminders can be used especially to modify the behaviour of [...] patients who are willing to take their medication but who forget it or are inaccurate,” they write.

And they may also provide a solution for those who deliberately don’t take their prescribed medication, “by stressing the importance of the intake in the message,” they suggest.

They also say that advances in technology may offer the possibility of longer-term benefits too.

“The increasing opportunities of new technologies make it possible to tailor reminding both in timing (only when needed) and in content (tailored messages). In this way, long-term improvements in medication adherence may be achieved,” they conclude.

Ben Adams is the reporter for Pharmafocus and InPharm.com and manages the DigiBlog site. He can be contacted via: email or Twitter.

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Patient-nurse relationship vital to treatment process

Published on May 8, 2012

Braden Dupuis

At the heart of any relationship, there lies an undercurrent of trust.

It’s a fact that is especially true when talking about the relationship between nurse and patient, and even more so when talking about nurses who specialize in treating those living with chronic hepatitis C.

While many living with hepatitis C can be cured, the road through treatment is a long and arduous one.

“It entails an injection a week and eating pills every day for 24 weeks,” explained Ronald Buckley, a 55-year-old man who has been living with the disease since 1986.

Buckley has been through treatment for the condition twice now.

He credits his own hepatitis support nurse for helping him push through when it seemed like he couldn’t go on.

“(She) was always there for me. On the emotional side she would counsel me in ways like, ‘It’s not the end of the world, this will change, give it some time and it wont be so bad’ … ‘keep going,’ was one of her big things,” he said.

“I got through the treatment, and so far I am virus free. They can’t find the virus in my system anymore, so that’s a good thing.”

Hepatitis C support nurses provide more than physical treatment to their patients.

They act as advocates, educators and counsellors, and are an essential facet of a patient’s treatment.

“I think a nurse’s support is vital for clients going through treatment successfully,” said Shelley Crawford, a hepatitis C support nurse in Prince Albert.

“I think your relationships with your clients become close because you work on all of those aspects of their care, and that’s extremely rewarding. When you see clients who have successfully went through treatment and they’ve cured their virus, it’s an indescribable feeling.”

While more than 250,000 Canadians live with the disease, it still carries the weight of the negative stigma associated with intravenous drug use and HIV.

“Oh boy … I thought it was the end of the world,” Buckley explained, about finding out he had contracted the disease in 1986.

“I thought … this is it, I’m gonna die. I compared it to HIV right away, and that was my big scare. Then I was told that it was nothing, it won’t hurt me, and a few years later down the road I found out that it will hurt me.

“There was a lot of mixed information about the disease back then, which has changed today. Today they know a lot more about it.”

While physicians and nurses are much more educated on the subject these days, hepatitis C still carries an inordinate amount of negative stigma.

“I still see a lot of stigma,” Crawford said.

“Clients have been bullied, they’ve been harassed, and they’ve even been fired in some experiences … lots of clients feel isolated and embarrassed about having the virus, no matter how they got it.

“We want everyone to know that it’s important to get tested, decrease the stigma, so we can stop the spread. Education is the big thing.”

Hepatitis C can be spread through a number of means, including blood transfusions occurring prior to 1992, tattoo needles and personal care items like toothbrushes, razor blades and nail clippers.

Many who carry the disease do not show symptoms, and it may take years for them to appear.

“Many people can have the virus and don’t even know it, so that’s why it’s so important for Canadians to be aware of all of the different ways it can be contracted,” Crawford said.

The good news is that many patients can be cured using new therapies currently available in Canada, though many come with some unpleasant side effects similar to those found in chemotherapy patients.

Having the right support network in place can prove to be invaluable in the long run.

“Very important. Very important to have the right network of support there, because I found that trying to do it alone is so hard,” Buckley explained.

“You end up isolated away because of the treatment. Because of the side effects of treatment, you tend to be sick a lot, so you’re isolated as it is, and if you isolate any more then it gets to be a problem.”

Buckley said his support nurse, along with his friends and family, gave him the strength to see it through.

“I find her more of a close friend than a nurse. Her door is always open. I can knock on the door and she always takes the time to say hi, come in, sit down and chat about what’s going on in my life… she’s always there,” he said.

“Even if I’m done treatment, I still drop in about once a week to have a chat with her, see where I’m going you know, just to check in. And she’s still there. I don’t think I would have made it through the treatment if she wasn’t there. The support and the compassion that she shows has always been what kept me going back.”

Crawford encouraged anyone who may think they have contracted the virus to get tested.

“Come out, get tested. For those who are living in silence with the virus, I really encourage those clients to come,” she said.

“Just come down and pop in and see us down at the clinic (at 101 15th Street E.)

“As support nurses we are there to support them on their treatment journey, both physically and emotionally, and at the end of the day that’s what we want — as many patients to be cured as possible.”

Buckley said that he wants everyone to know that anybody can contract the virus, and with the right support network, anybody can beat it.

“Hepatitis C is a treatable disease,” he said.

“We can function in the world as normal human beings. Just because we have it doesn’t mean that we need to be locked away in a closet.”

braden.dupuis@tc.tc

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Scientists make breakthrough in study on bile duct cancer with discovery of new gene mutations

Bile duct cancer is a deadly type of liver cancer with a poor prognosis. The latest breakthrough could help scientists learn more about the disease, and potentially pave the way for improved treatments. Image: Raycat/iStockphoto

• Asian researchers report the first comprehensive genomic study of Bile Duct Cancer, a deadly type of liver cancer caused by liver fluke infection
• Liver flukes, which are food-borne parasites, are thought to infect over 6 million people in Thailand
• Joint Singapore-Thai team uncovers new critical genes responsible for the onset of Bile Duct Cancer.

Singapore, 7 May 2012 - A combined team of scientists from Singapore and Thailand has made a significant breakthrough in understanding the cause of bile duct cancer, a deadly type of liver cancer. Using the latest genomic technologies, the researchers identified several new genes frequently mutated in bile duct cancers, paving the way for better understanding on how bile duct cancers develop.

The Singapore-Thailand team was led by Professor Teh Bin Tean, Associate Professor Patrick Tan, Associate Professor Steve Rozen (Duke-NUS Graduate Medical School of Singapore) and Professor Vajarabhongsa Bhudhisawasdi from Thailand’s Khon Kaen University. The breakthrough came after two years of intensive research, which saw scientists from Singapore visiting the villagers in northern Thailand, and Thai researchers coming to Singapore to work in NCCS laboratories. The discovery was published online on 6 May 2012 in Nature Genetics.

Bile Duct Cancer, or Cholangiocarcinoma, is a fatal cancer with poor prognosis. Accounting for 10 to 25 per cent of all primary liver cancers worldwide, bile duct cancer is a prevalent disease in Southeast Asia, particularly in the Northeast of Thailand which sees about 20,000 new cases each year. The high incidence in Thailand is attributed to long-term consumption of raw fish that is infected with liver flukes, which are food-borne parasites found in fish. Liver fluke infections are widespread in Northeast Thailand, where they are thought to occur in over 6 million people. Once eaten, the flukes accumulate in the bile ducts of the human host, causing constant infection and the onset of cancer.

Professor Teh, who was a recipient of the Singapore Translational Research (STaR) Investigator Award in 2009 and the Director and Principal Investigator of the NCCS-VARI Translational Cancer Research Laboratory at the National Cancer Centre Singapore, said the study will pave the way for a better understanding of the roles that newly identified genes play in the development of bile duct cancer. "This discovery adds depth to what we currently know about bile duct cancer. More important is that we are now aware of new genes and their effects on bile duct cancer and we now need to further examine their biological aspects to determine how they bring about the onset of Cholangiocarcinoma."

Using state of the art DNA sequencing platforms, the researchers analysed eight bile duct cancers and normal tissues from Thai patients, and discovered mutations in 187 genes. The team then selected 15 genes that were frequently mutated for further analysis in an additional 46 cases. Many of these genes, such as MLL3, ROBO2 and GNAS, have not been previously implicated in bile duct cancers.

"With this finding we now know much more about the molecular mechanisms of the disease and we can draw up additional measures that can be taken while we identify the most appropriate treatment protocols. We are talking about the potential to save many lives in Thailand," said Professor Vajarabhongsa Bhudhisawasdi, Director of the Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University of Thailand. "Also, this study shows that we can work closely with our counterparts in other countries and share our expertise and experience to improve the lot for the people."

The researchers also compared the bile duct cancers to other related cancers of the liver and pancreas. Surprisingly, they found that the bile ducts cancers shared certain similarities with pancreatic cancer. "This research provides a strong direction for future studies," said Associate Professor Patrick Tan, faculty member of the Cancer and Stem Cell Biology Programme at Duke-NUS. "Cholangiocarcinoma and Pancreatic Duct Adenocarcinoma appear to share more molecular similarities than earlier studies had indicated, and suggest that there are common biological pathways between the two cancers. By studying these pathways, we can then shed more light on how these tumours develop."

Dr Chutima Subimerb, a Thai scientist involved in the project, said she was pleased with the collaboration and to be able to participate in this health diplomacy project. "We are very privileged to be able to work alongside Prof Teh and the other scientists from Singapore. By pooling our resources we were able to make this discovery which will have very wide impact on the people, especially the poor people who have been eating the fish that they catch from the ponds and rivers in the region. I believe this is only a first step and we will see even more collaborations in time to come between our two countries in the field of scientific research."

The research was funded by the Ministry of Health’s National Medical Research Council, Millennium Foundation, Lee Foundation, National Cancer Centre Research Fund, Duke-NUS Graduate Medical School Singapore, Cancer Science Institute Singapore, Research Team Strengthening Grant, National Genetic Engineering and Biotechnology Center and the National Science and Technology Development Agency (Thailand).

About NCCS

The National Cancer Centre Singapore (NCCS) is the cancer centre dedicated to providing a holistic and multidisciplinary approach to cancer treatment and patient care. We treat almost 70 per cent of the public sector oncology cases. Through the sub-specialisation of its oncology, patients can receive the best in treatment and care. NCCS is engaged in cutting-edge clinical and translational research which has received several international acclaims. The national centre is accredited by the Joint Commission International in 2010 for quality patient care and safety. NCCS, which is set to be a global leading institution, also offers specialist training programmes to other medical institutions here and overseas.

About Duke-NUS Graduate Medical School Singapore

The Duke-NUS Graduate Medical School Singapore (Duke-NUS) was established in 2005 as a strategic collaboration between the Duke University School of Medicine, located in N.Carolina, USA and the National University of Singapore (NUS). Duke-NUS offers a graduate entry, 4-year M.D. (Doctor of Medicine) training program based on the unique Duke model of education, with one year dedicated to independent study and research projects of a basic science or clinical nature. Duke-NUS also offers M.D/PhD and PhD programs. As a player in Singapore’s biomedical community, Duke-NUS has identified five Signature Research Programs: Cancer & Stem Cell Biology, Neuroscience and Behavioral Disorders, Emerging Infectious Diseases, Cardiovascular & Metabolic Disorders, and Health Services and Systems Research. For more information, please visit www.duke-nus.edu.sg.

About Khon Kaen University of Thailand

Khon Kaen University (KKU) was one of four regional universities established in 1964 as part of a decentralized development plan for higher education in Thailand. The campus is located in the Northwestern sector of Khon Kaen, just a few kilometers from the center of the city. Situated in a most attractive park, the campus covers approximately 900 hectares. From small beginnings, KKU has grown enormously and is today home to eighteen faculties, three colleges, 7 academic support centers, a hospital, a research institute and 22 research excellent centers. In addition several new institutes are currently in pipeline and will, in time, open the University's door further to the public and increase its roles, responsibilities and commitments to the region around. Currently the number of students is approximately 40,000 (including 9,800 postgraduates and about 290 students from overseas).

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Biolex Sells LEX System to Synthon and Initiates Sale of Locteron(R)

PRESS RELEASE

May 7, 2012, 9:03 a.m. EDT

PITTSBORO, NC, May 07, 2012 (MARKETWIRE via COMTEX) -- Biolex Therapeutics, Inc. announced that it has sold its LEX System, a proprietary platform for the development and production of biologics, to Synthon, a Netherlands-based specialty pharmaceutical company. Also included in the sale were two preclinical product candidates uniquely enabled by the LEX System: BLX-301, a humanized and glyco-optimized anti-CD20 antibody for the treatment of non-Hodgkin's B-cell lymphoma and other B-cell malignancies; and BLX-155, a direct-acting thrombolytic designed to dissolve blood clots in patients. Financial terms of the sale will not be disclosed.

Locteron Sale Biolex also announces that it has initiated the sale of its remaining Phase-3 ready asset, Locteron(R) controlled-release interferon for the treatment of HCV and HBV.

Locteron, controlled-release interferon alpha 2b, is designed to offer key advantages compared to currently approved interferon products. In Phase 2b clinical trials in hepatitis C (HCV) Locteron demonstrated statistically significant reductions in flu-like symptoms, reduced rates of depression, and cutting in half the number of injections required compared to pegylated interferon. It is estimated that current worldwide sales of interferon are approximately $2.5 billion. Flu-like symptoms and depression are the two most important side effects of interferon and limit treatment adherence.

Locteron incorporates an advanced controlled-release drug delivery technology that allows dosing once every two weeks. This is considerably more convenient than the currently approved interferon products, Pegasys(R) and PEG-Intron(R), each of which are immediate release and require dosing every week. More importantly, Locteron's controlled-release mechanism results in the gradual release of interferon alpha 2b to patients over the duration of two weeks and avoids the early peak plasma levels of the active interferon that characterize the pegylated interferons. This controlled-release mechanism is designed to reduce the frequency and severity of flu-like symptoms and depression commonly experienced by patients treated with pegylated interferons.

"We believe that even if all-oral interferon-free regimens are eventually approved, a Locteron-containing regimen will achieve at least equal efficacy (SVR rate), but likely with a shorter duration of treatment that is well tolerated by patients. A regimen with Locteron will be much more cost-effective, and in a payer driven world, that means it will be preferentially reimbursed," said Jan Turek, President and Chief Executive Officer of Biolex. "Many countries may require the use of a more cost-effective interferon-containing regimen as first-line therapy before reimbursing a more expensive interferon-free combination. There are already signs of this dynamic as several cost-effectiveness studies have recently been published that claim that using direct-acting anti-viral agents is not cost-effective for patients with a specific host genotype who are very interferon responsive. Beyond HCV, HBV is a smaller, albeit solid and growing opportunity for Locteron, as an interferon-based treatment in HBV can effectively provide a 'cure' by sero-conversion of the patient, a preferred outcome as opposed to the current chronic, life-long therapy keep HBV suppressed."

Locteron has strong patent protection through 2028, and has worldwide freedom to operate (FTO). Biolex intends to sell the worldwide development and commercialization rights to Locteron.

Locteron is an investigational therapeutic candidate and has not been approved for sale by the United States Food and Drug Administration or by any international regulatory agency.

About Biolex Therapeutics Biolex is a privately held biopharmaceutical company that developed the patented LEX System to manufacture follow-on biologics, hard-to-make therapeutic proteins and optimized monoclonal antibodies. The LEX System is a novel technology that genetically transforms the aquatic plant Lemna to enable the production of biologic product candidates. The company's product candidates were designed to provide best-in-class efficacy/tolerability profiles while incorporating proven mechanisms of action. Biolex's lead product candidate, Locteron, has completed five clinical trials, including two Phase 2b clinical trials for the treatment of chronic hepatitis C

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Will we ever have an HIV vaccine?

Image by Dr. A. Harrison; Dr. P. Feorino

May 7th, 2012 by Ed Yong

For around 30 years we have lived under the spectre of HIV. In the early 1980s, the mysterious appearance of symptoms that would later be known as AIDS led to unprecedented efforts to unmask the cause. On 23 April 1984, Margaret Heckler, the US Secretary of Health and Human Services, told the world that scientists had identified the virus that was the probable cause of AIDS. She was correct. She also said that a vaccine would be “ready for testing in approximately two years.” She was wrong.

Despite 28 years of research, there is still no vaccine that provides effective protection against HIV, and in that time around 25 million people have died of HIV-related causes. To understand why creating a vaccine is so hard, you need to understand HIV. This is no ordinary virus. Scientists who study it speak of it with a mix of weary frustration and awed reverence.

The virus is the most diverse we know of. It mutates so rapidly that people might carry millions of different versions of it, just months after becoming infected. HIV’s constantly changing form makes it unlike any viral foe we have tried to thwart with a vaccine. “Almost every vaccine that’s been developed protects against a small number of strains,” says Gary Nabel, Director of the Vaccine Research Center at the US National Institute of Allergy and Infectious Diseases (NIAID).

Vaccines train the immune system to recognise part of a virus, creating a long-term armada of antibodies that seek and destroy the invader, should it ever show its face. For HIV, the most obvious target is gp120, the surface protein that it uses to attach itself to human cells. But gp120 also constantly changes shape, making it difficult to recognise. It also comes in clusters of three that are shielded by bulky sugar molecules, hiding it from the immune system.

On top of that, HIV targets immune cells, the very agents that are meant to kill it. And it can hide for years by shoving its DNA into that of its host, creating a long-term reservoir of potential infection.

So, creating an HIV vaccine is like trying to fire a gun at millions of shielded, moving targets. Oh, and they can eat your bullets.

Uphill struggle

So far, nature has provided little reassurance that a vaccine against HIV is even possible. For virtually every other microbe, there are people who naturally recover from their infections. “Nature itself provides the proof-of-concept experiment. It has told you that the body can inherently do this,” says Anthony Fauci, an immunologist who heads NIAID. But when it comes to HIV, “we have the astounding reality that, with more than 30 million people living with the virus, there is not a single documented case of someone mounting an immune response to completely eliminate the virus from their body.” Some people have the right genetic qualities to keep the virus in check, but no one clears it.

Given these challenges, it should be no surprise that vaccine research has been, to quote one researcher, a “Sisyphean onslaught of disappointments”. Only three potential candidates have made it through clinical trials. Vaxgen’s AIDSVAX vaccine, consisting of two fragments of the gp120, failed to provide any protection. Merck’s v520 vaccine, consisting of a harmless cold virus carrying three HIV genes, fared even worse. It was meant to marshall immune cells called T-cells to kill off infected cells. It failed. Worse still, the trial had to be stopped early because vaccinated people seemed to be more susceptible to infections, for reasons we still do not fully understand.

The only sliver of success came in 2009. A Thai trial of more than 16,000 people – the largest one yet – had been testing a combination of two vaccines: a bird virus containing three HIV genes, which was meant to prime the immune system, and a tweaked version of the AIDSVAX vaccine to act as a booster. Since both vaccines had failed individually, critics argued that the trial was a waste of time and money. But to many people’s surprise, the combination reduced the risk of infection by 31% – a statistically significant effect, though too low for a useable vaccine. (For comparison, the measles and polio vaccines are around 95% effective).

Some scientists were sceptical about the results, noting that the protection was short-lived and confined to people at low risk of infection. Others saw a ray of hope after years of frustration, a sign that a vaccine is in principle possible. Either way, the trial was confusing, especially since the vaccines did not reduce the levels of virus in infected people. Scientists are still trying to work out why the vaccine had any effect at all.

Renewed hope

But despite the muted results from existing trials, scientists in the field are unfazed. The reason, according to Wayne Koff from the International AIDS Vaccine Initiative, is that since the Thai results were announced, “the field that has begun to undergo a renaissance.”

It turns out that many HIV patients carry secret weapons – “broadly neutralising antibodies” – that can attack a wide range of HIV viruses. For these patients, it is too late. Their infections are already in full swing and the virus can mutate around their defences. But the discovery proved that HIV’s vaunted diversity is not the roadblock for vaccines that many scientists feared. If we taught the immune system to make these antibodies early, we could destroy the virus before it gained a foothold.

It is possible to isolate the right antibodies because we now know the shape of HIV’s surface proteins, down to the atomic level. Nabel used this knowledge to identify parts that stay the same while the rest of the virus shifts and mutates. These non-mutating regions are likely to be vital areas that cannot change without causing problems. He searched patients’ blood to find antibodies that target these conserved regions, and cells that make those antibodies. In 2010, he found three: two of which could neutralise 90% of HIV viruses. Other scientists, such as Dennis Burton of the Scripps Research Institute, have made similar discoveries using similar methods.

Nabel’s vision is a cocktail of these super-antibodies that target different parts of the virus, cutting off its evolutionary escape routes. He hopes to start clinical trials of his first-generation antibodies by early 2013, and he says is close to producing a second-generation of even heavier hitters that he thinks are two to three years away from early trials.

Vaccine researchers are also working on ways of stimulating our T-cells to kill infected cells at an early stage. This was the strategy behind Merck’s failed v520 vaccine, but scientists have since found better ways of smuggling viral genes into cells, and targeting them at the tissues most likely to be infected first. Both approaches would be complementary: “I think we would need a combination of broadly neutralising antibodies and a broad and robust T-cell response,” says Koff.

Compelling need

There is no telling when, or indeed if, these strategies will yield results, but what is certain is that the need for a vaccine will not diminish. There are many ways of preventing HIV infection, including condoms, microbe-killing gels, and the use of treatments as soon as people get infected. “We’d be going in the right direction with the tools we already have,” says Fauci. “But if we added a vaccine to the toolkit, even if it wasn’t 90% effective, you could have a major additive effect. There really is a compelling need for one.”

It may seem frustrating that decades of research have yielded nothing that satisfies this compelling need. But everything in the pipeline has depended on a steadily accumulating knowledge of the virus over those years. And as much as we know about the virus, and our immune response to it, there is still a great deal to learn. Also consider this. It took 47 years to create a vaccine for polio after the microbe behind it was identified. The measles vaccine took 42 years. The hepatitis B vaccine was a positive sprint at 16 years. “Twenty-eight years isn’t an inordinate amount of time,” says Fauci.

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Early Elevated Hiv Infection Risk in Some Step Study Participants Who Received Vaccine; Risk Decreased Over Time

ScienceDaily (May 7, 2012) — A long-term follow-up analysis of participants in the Step Study, an international HIV-vaccine trial, has confirmed that certain subgroups of male study participants were at higher risk of becoming infected after receiving the experimental vaccine compared to those who received a placebo. The vaccine used in the study did not contain the HIV virus, but it did contain HIV genes which were delivered to cells using a vector that employed a type of cold virus known as adenovirus serotype 5 (Ad5).

Of the 1,836 men examined in this study, 172 became infected with HIV. Within 18 months of enrollment or one year after the last vaccination, men who had neutralizing antibodies to Ad5 or who were uncircumcised, or both, had a two- to four-fold increased risk of acquiring an HIV infection, according to findings published in the May 4 online edition issue of the Journal of Infectious Disease.

However, the study also found that the risk level waned after about 18 months to be equal to that of volunteers who received a placebo.

Why this association occurred, what the biological mechanisms were and why the risk of infection lessened with time are unknown and require more study, according to Ann Duerr, M.D., a member of the Vaccine and Infectious Disease Division of Fred Hutchinson Cancer Research Center, who led the data analysis.

"There seems to be some kind of biologic phenomena that affects infection risk," she said.

The current study indicated that self-reported risk behaviors, such as unprotected sex, did not differ significantly between the vaccine and placebo arms of the Step trial.

The research also confirmed there was no elevated risk of infection in vaccinated men who were circumcised and who were Ad 5 seronegative (men who had no neutralizing antibodies to the adenovirus vector used in the vaccine). An earlier interim analysis of the Step Study data, done after immunizations in the vaccine trial were halted in 2007, also detected this relationship between Ad5 sero-status and vaccine-associated HIV risk. Today, only men who are circumcised and Ad5 seronegative are eligible to receive experimental HIV vaccines that use the adenovirus serotype 5 as a biological delivery mechanism.

Duerr said scientists need a better understanding of what happened biologically to men who became infected, before those who are uncircumcised or seropositive for Ad 5 are enrolled in future vaccine trials in which the adenovirus serotype 5 vector is used. Ad 5 is used as a vector because it elicits a strong immune response by CD8 T cells. These cytotoxic T lymphocytes are thought to be responsible for controlling HIV infection.

In the current study, researchers analyzed data from male Step Study participants who enrolled in a trial that provided follow-up for up to four years after they enrolled in the Step study, or until Dec. 31, 2009, whichever came first.

The Step Study enrolled 3,000 male and female volunteers in North and South America, the Caribbean and Australia between 2004 and 2007. Injections in the study were halted in September 2007 after researchers detected a lack of effectiveness by the vaccine to prevent HIV acquisition or reduce HIV viral load in infected participants, and a higher-than-expected number of HIV infections in certain subgroups of vaccinees.

In addition to Hutchinson Center researchers, scientists from the San Francisco Department of Public Health, University of Washington, Emory University, Care Resource, Merck Research Laboratories and two Peruvian institutions co-authored the paper. The study was funded by Merck Research Laboratories and the National Institutes of Health.

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Senate HELP Committee to Hold Hearing on Prize Fund for HIV/AIDS Act

May 7, 2012 By Mike Palmedo

On May 15, the Senate Health, Education, Labor and Pensions Committee will hold a hearing on S. 1138, the Prize Fund for HIV/AIDS Act. The bill, introduced a year ago by Sen. Sanders, would provide direct support to innovators while allowing immediate generic competition upon approval of new treatments for HIV/AIDS.

As explained in a fact sheet from Sanders’ office: “The Prize Fund would reward useful investments in R&D for new treatment and manufacturing processes, and would lower the overall costs of treatments for HIV/AIDS by allowing introduction of generic medicines for HIV/AIDS as soon as they enter the market. The Prize would be co-funded by the federal government and private health insurance programs at 0.0002 of the GDP of the United States, equaling more than $3 billion per year at current levels. Patents would still be available for HIV/AIDS inventions, and valuable in making claims against the Prize Fund, but could not be used to block generics entering the market. Generic competition among competitive suppliers is expected to lower the cost of drugs by more than $7 billion per year for the U.S. domestic market, with the saving shared by health insurers (both public and private) and patients.”

For more see:

• Fact Sheet from Sen. Sanders’ Office
• Text of S.1138: The Prize Fund for HIV/AIDS Act
• Blog by James Love on Sanders’ introduction of this (and another) Prize fund bill

Source

Scarring Cells Revert To Inactive State As Liver Heals

UC San Diego School of Medicine

A photomicrograph of cirrhotic liver tissue, with extensive fibrotic scarring (stained blue).

Released:5/7/2012 3:40 PM EDT
Source:University of California, San Diego Health Sciences

Research with mice reveals possible strategy to reverse fibrosis in liver and other organs

Newswise — An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, report that significant numbers of myofibroblasts – cells that produce the fibrous scarring in chronic liver injury – revert to an inactive phenotype as the liver heals. The discovery in mouse models could ultimately help lead to new human therapies for reversing fibrosis in the liver, and in other organs like the lungs and kidneys.

The work is published in the May 7, 2012 online Early Edition of the Proceedings of the National Academy of Sciences.

“The take-away message is two-fold,” said David A. Brenner, MD, vice chancellor for Health Sciences, dean of the UC San Diego School of Medicine and senior author of the paper. “First, we’ve shown that liver fibrosis is markedly reversible and we now better understand how it happens. Second, we can start looking for ways to direct active myofibroblasts to stop producing scar, and become inactive. We can focus on developing drugs that promote cell change and regression. It raises the bar for prospective treatment tremendously.”

Liver fibrosis is the 12th leading cause of death in the United States. It is the result of chronic liver injury caused by such agents as the hepatitis B and C viruses, alcoholic liver disease and non-alcoholic steatohepatitis. The condition is manifested by extensive scarring of liver tissue and the organ’s progressive inability to filter body toxins. Liver fibrosis precedes the development of liver cancer. Often, the only treatment for end-stage liver fibrosis is an organ transplant.

Fibrosis begins when infectious agents or excessive alcohol consumption trigger activation of hepatic stellate cells (HSCs), which normally act as quiescent storage units for nutrients like vitamin A in the liver. Once activated, these HSCs acquire characteristics of another cell type called myofibroblasts, which are characterized by their abundant production of extracellular matrix proteins such as collagen. These proteins accumulate as scar tissue, rendering the organ progressively dysfunctional.

However, if the source of the liver injury is successfully treated or eliminated, the liver can repair itself. In part, this is due to the activated HSCs undergoing apoptosis (programmed cell death) and being removed by other cells. But UC San Diego scientists say that, in tests using a mouse model, as many as half of all activated HSCs persist. They do not die, but rather revert to an inactive phenotype during fibrotic regression.

“After one month of regression, these cells have stopped producing collagen. They’ve upregulated some of the genes associated with quiescence and returned to their normal location in the liver,” said Tatiana Kisseleva, MD, PhD, an assistant research scientist and first author of the study.

It’s not clear why these myofibroblasts survive. Also, scientists note the reverted myofibroblasts do not completely return to their original quiescent state. “They’re still more susceptible to repetitive injury than original quiescent HSCs,” said Kisseleva, who noted future tests will investigate whether additional reversion occurs with more time.

Kisseleva suggested the findings present another avenue for treating liver fibrosis, especially in possibly reverting fibrosis and cirrhosis, which accounts for roughly 27,000 deaths in the United States annually.

Fibrosis occurs in other organs as well, such as the kidneys and lungs, with comparable deadly effect. Recent studies indicate fibrotic reversibility in these organs as well. “Our findings are applicable to other fibrosing organs,” said Kisseleva. “Instead of killing damaged cells, we might be able to de-activate them and revert them to healthy originals.”

Co-authors of the study are Min Cong, Chunyan Jiang, Keiko Iwaisako, Brian Scott and Wolfgang Dillmann, Department of Medicine, UC San Diego; YongHan Paik, Department of Medicine, UC San Diego and Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, South Korea; David Scholten, Department of Medicine, UC San Diego and Department of Medicine III, University Hospital Aachen, Germany; Thomas Moore-Morris and Sylvia M. Evans, Skaggs School of Pharmacy and Pharmaceutical Science, UC San Diego; Hidekazu Tsukamoto, Keck School of Medicine, University of Southern California.

Source

Intensive Follow-up Reduces Mortality from Hepatocellular Cancer

By: NEIL OSTERWEIL, Family Practice News Digital Network

05/07/12

ORLANDO – Intensive follow-up of patients who have undergone surgery for hepatocellular carcinoma reduces deaths from tumor recurrence and metastases, Dr. Timothy M. Pawlik said at a symposium sponsored by the Society of Surgical Oncology.

Data from surveillance programs for hepatocellular carcinoma (HCC) and empiric data from centers treating colorectal liver metastases (CRLM) suggest that HCC tends to recur locally, and that recurrent HCC and CRLM, if caught early, can be successfully controlled with a variety of therapeutic options, said Dr. Pawlik, associate professor of surgery and oncology, and hepatobiliary surgery program director at Johns Hopkins Medical Center, Baltimore.

"I would favor high-intensity surveillance for patients with hepatocellular carcinoma. This argument is based on level 1 data showing that high-intensity primary surveillance decreases mortality for patients who have cirrhosis," he said.

Although there is a high HCC recurrence rate following surgery, most recurrences will be contained within the liver, and may be successfully treated with salvage transplantation, ablation, or intra-arterial therapy.

"But if we miss that opportunity and patients recur with advanced disease, all those options are off the table, and their prognosis is abysmal," Dr. Pawlik said.

According to National Cancer Institute data, liver cancer holds the dubious distinction of being the fastest growing cancer in terms of death rate in the United States, outpacing lung cancer in women, esophageal cancer, and thyroid cancer.

Risk factors for HCC include cirrhosis from any cause (hepatitis B and C viruses, alcoholism, nonalcoholic fatty liver disease), hepatitis B primary infection (with or without cirrhosis), and inherited metabolic diseases such as hemochromatosis, alpha-1 antitrypsin deficiency, glycogen storage disease, or tyrosinemia.

"Most patients who have HCC don’t simply have a cancer; they also have significant underlying cirrhosis, so when thinking about the approach to HCC, we have to be thinking about all of the tumor-specific factors such as tumor size, location, and number, and we also have to be thinking about all of the liver-specific factors," Dr. Pawlik said.

Surgical treatment options include resection for HCCs of all sizes; transplantation, for single lesions 5 cm or smaller, or up to three lesions of 3 cm or less or advanced cirrhosis; and ablation for small lesions or inoperable or unresectable tumors as a bridge to transplant.

In various series, overall 5-year survival following resection ranges from 42% to 62%, and following transplantation from 57% to 75%.

But as Dr. Pawlik and colleagues noted in a 2008 study, disease-free survival following resection for HCC is only half of the percentage after transplantation (40% vs. 82%, P less than .01). (J. Gastrointest. Surg. 2008;12:1699-1708).

Intrahepatic recurrence is most frequent among patients with hepatitis C infection, but also occurs with hepatitis B and C coinfection, and hepatitis B alone. A subset of patients who have undergone transplantation (about 20%) will also have recurrence, Dr. Pawlik said.

National Comprehensive Cancer Network guidelines for follow-up of patients with HCC after resection or transplantation include imaging every 3-6 months for 2 years, then every 6-12 months thereafter, and testing of alpha-fetoprotein (AFP) level, if initially elevated, on the same schedule, he noted.

For example, a trial that included 18,816 hepatitis B carriers in China randomized to either intensive surveillance with AFP level and twice-yearly ultrasound versus no screening showed that the intensive surveillance was associated with a significantly lower rate ratio for mortality compared with no screening (RR 0.63) (J. Cancer Res. Clin. Oncol. 2004;130:417-22).

Similar evidence has been found to support intensive follow-up for colorectal cancers, for which there is effective therapy for recurrent disease, Dr. Pawlik noted.

Unlike pancreatic cancer or melanoma, where recurrences tend to be distant metastases, hepatocellular carcinoma is more frequently locally recurrent. It was found that 64%-80% of patients with cirrhosis had an intrahepatic recurrence within 5 years of HCC resection.

In one study, investigators found that 60%-70% of tumors recurred within 2 years, and 30%-40% of patients with recurrences had de novo tumors (J. Hepatol. 2003;38:200-7).

"For patients who have hepatocellular carcinoma, there are two reasons to [monitor] these patients closely. One is that they may truly have recurrence, and two is that a subset of these patients will develop new de novo disease in the cirrhotic liver," Dr. Pawlik said.

Treatment options for late recurrences are very limited and not very effective, he added. Sorafenib (Nexavar) is approved for unresectable HCC, but in the phase III SHARP trial was associated with an improvement in median overall survival of only 2.8 months vs. placebo (P = .00058) (N. Engl. J. Med. 2008;359:378-90).

In contrast, early recurrences generally respond to repeat resection, salvage transplantation, radiofrequency ablation, or transarterial chemoembolization, Dr. Pawlik noted.

Dr. Pawlik said he has no relevant disclosures.

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Gilead’s Truvada Pill Is Safe for HIV Prevention, FDA Says

By Ryan Flinn and Shannon Pettypiece - May 8, 2012 10:28 AM ET

Gilead Sciences Inc. (GILD)’s pill Truvada was safe and effective when used to protect uninfected people from getting HIV, U.S. regulators said in a report indicating the main concerns are when and how it should be used.

Truvada was “well tolerated” and its ability to reduce the risk of infection was backed by two studies, the Food and Drug Administration staff said in a report today. Gilead, based in Foster City, California, is seeking to sell the drug as the first pill to keep people from becoming infected.

The FDA asked its advisers to suggest who should get Truvada; what testing would be needed for administration; and what educational material should be used for patients and doctors. The advisers will meet May 10 to discuss the drug, the subject of debates over its appropriate use and cost.

Decisions to prescribe Truvada “should carefully weigh the individual risks for acquiring HIV, their understanding of the importance of adherence to medication, and their potential for development of renal toxicity,” the FDA staff said today in a report on the agency’s website. Education and counseling will be“critically important.”

Gilead fell less than 1 percent to 9:57 a.m. New York time. The FDA isn’t required to follow what the advisory panel suggests.

AIDS Debate

Debate over the appropriate use of the drug has divided the AIDS community. Some AIDS advocacy groups say the drug will be a valuable tool for reducing new cases, particularly within stable partnerships where one person has AIDS and the other doesn’t. Others said it may lead to more infections, lower condom use and might build resistance to the medicine.

About 415,000 Americans are at high risk for contracting HIV, the Human Immunodeficiency Virus that leads to AIDS, according to the U.S. Centers for Disease Control and Prevention, based in Atlanta.

“Thirty years into the epidemic we can’t dismiss any new options,” James Loduca, a spokesman for the San Francisco AIDS Foundation, said in an interview. “This won’t end AIDS by itself, but we can’t end it without this.”

Loduca said condoms aren’t enough to stem the tide of new infections, and using Truvada as a preventative measure would help if taken correctly.

While the number of people infected with HIV rose to 34 million worldwide in 2009, the virus that leads to AIDS, once a death sentence, can be reduced to low levels in the blood with use of combination antiviral medicines such as Truvada.

Condom Use

Michael Weinstein, president of the AIDS Healthcare Foundation, said approval and prescription of Truvada as a preventative may lead to less condom use and more infections, as well as increased resistance to the drug.

“Why would you take this medication if you intended to use condoms?” he said. “You’ve got to be really paranoid about your pants falling down to wear a belt and suspenders.”

His organization sued the FDA last year after the agency rejected its Freedom of Information act request for correspondence between regulators and Gilead. Weinstein said the studies don’t prove that the pill is effective enough to warrant approval. The AIDS Healthcare Foundation has lined up speakers for the public hearing later this week to oppose its preventative use, Weinstein said.

Barry Zingman, medical director at the AIDS Center at Montefiore hospital in the Bronx, one of the largest treatment centers in New York, said he hopes the drug is approved and plans to offer it to some patients.

Pill ‘More Acceptable’

“If condoms were 100 percent effective and useful we wouldn’t have HIV at all,” Zingman said in an interview. “The reality is many people don’t like to use condoms or won’t, and taking a pill can be a lot more acceptable to them.”

He said his big concern is the drug’s more than $11,000 a year price tag.

“People are really interested in the concept, but there have been issue related to insurance coverage,” Zingman said.“Approval would make a significant advance in insurance coverage.”

Aetna Inc. spokeswoman Tammy Arnold and WellPoint Inc. spokeswoman Lori McLaughlin said their companies would consider covering the treatment as a form of prophylaxis if approved by the FDA. UnitedHealth Group Inc. declined to comment.

Medicare, the federal program for the elderly and disabled, and Medicaid, the joint state-federal plan for the poor, typically reimburse for all FDA-approved indications.

High-Risk Treatment

If approved, the drug would mostly be given to people at high risk for infection, like men who have sex with men, intravenous drug users and sex workers, said Ken Mayer, medical research director at the Fenway Institute, the largest AIDS treatment center in New England. It would typically be given for a limited period of time, he said.

“I think it would be a mistake for the FDA not to approve this indication,” Mayer said. “If we can figure out how to use this most effectively we can really put a dent in the number of new infections.”

In a study of men who have sex with men, the drug reduced the risk of infection by 42 percent, though adherence in the trail was low, the agency said. In a study of heterosexual couples where one person was infected, the risk was reduced by 75 percent.

To contact the reporters on this story: Ryan Flinn in San Francisco at rflinn@bloomberg.net; Shannon Pettypiece in New York at spettypiece@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

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Aethlon Medical Reports Undetectable Hepatitis C Virus (HCV) in Genotype 1, Genotype 3, and Genotype 5 Patients Treated with Hemopurifier® Therapy

PRESS RELEASE

May 8, 2012, 9:30 a.m. EDT

SAN DIEGO, May 8, 2012 /PRNewswire via COMTEX/ -- Aethlon Medical, Inc. , the pioneer in developing selective therapeutic filtration devices to address infectious disease, cancer and other life-threatening conditions, reported today that the presence of Hepatitis C virus (HCV) is currently undetectable in all infected patients that have been treated with the Aethlon Hemopurifier® in combination with peginterferon+ribavirin (PR) drug therapy and monitored for at least ninety days.

In a study conducted at the Medanta Medicity Institute (Medicity), HCV-infected individuals were enrolled to receive up to three, six-hour Hemopurifier® treatments during the first three days of PR drug therapy. The Medicity is a $360 million multi-specialty medical institute established to be a premier center for medical tourism in India. The Aethlon Hemopurifier® is a first-in-class medical device that selectively targets the rapid clearance of HCV from the entire circulatory system to improve benefit, dose, duration and tolerability of drug therapies.

In the Medicity study, Aethlon reported that Hemopurifier® therapy has been well tolerated and without device-related adverse events in nine treated patients. Of these nine patients, six patients were infected with HCV genotype-1; two patients were infected with HCV genotype-3; and one patient was infected with HCV genotype-5. Of the nine reported patients, seven have been monitored for more than ninety days. All seven currently maintain undetectable viral load, including three patients who have been monitored for 48-weeks. Two patients initiated Hemopurifier® therapy on April 18th and April 30th, and therefore have not yet been monitored for extended viral load suppression.

The Immediate Impact of Hemopurifier® Therapy

In addition to demonstrating safety and early efficacy against multiple HCV genotypes, a clinical objective of the Medicity study was to evaluate whether the Hemopurifier® could accelerate HCV eradication to levels associated with treated patients who achieve the highest rate of viral cure, including individuals that previously failed or relapsed PR drug regimens. In the study, Aethlon observed that viral load depletion during the Hemopurifier® + PR drug therapy phase was greatest in hard-to-treat genotype-1 patients with high viral load. In one treated patient, baseline HCV RNA dropped from 5,800,000 IU/ml to 1,840 IU/ml when measured after the third day of Hemopurifier® + PR therapy, representing a 3.49 log or 99.96% reduction of viral load. In another patient, baseline HCV RNA dropped from 8,760,000 IU/ml to 4,665 IU/ml when measured on day-3, representing a 3.27 log or 99.96% reduction. By contrast, a moderate viral load Hemopurifier® patient with baseline HCV RNA of 1,340,000 IU/ml dropped to 54,900 IU/ml when measured on day-3, representing a 1.38 log or 95.9% reduction.

As a point of reference, the landmark IDEAL Study of 3,070 HCV genotype-1 patients documented that less than 5% of treated patients will achieve a 2-log or greater reduction of viral load when measured 7-days after the start of PR drug therapy. While the IDEAL study did not report day-3 viral load, a 2-log+ reduction at day-7 is a rare occurrence defined as an immediate virologic response (IVR). The IDEAL study confirms the viral cure or sustained virologic response rate of IVR patients to be greater than 90%. Based on Medicity treatment outcomes, Hemopurifier® therapy had a significant impact in accelerating HCV eradication in high viral load patients.

Capacity of the Hemopurifier® to Capture HCV During Treatment

As the result of discussions with reviewers at the Center for Devices and Radiological Health (the FDA branch responsible for approving medical devices in the US), Aethlon recently expanded the Medicity protocol to establish a data point that would quantify the amount of HCV captured within the Hemopurifier® during a single treatment. In one analyzed cartridge, researchers recovered and measured that approximately 300 billion (300,000,000,000) copies of HCV had been captured within the Hemopurifier® during a single six-hour treatment at the Medicity. Beyond the impact of inhibiting progeny virus replication, the viral capture data point defines the contribution Hemopurifier® therapy can provide to current and future antiviral drug treatment regimens. Aethlon considers this data point to be unprecedented as the previous ability to measure the benefit of HCV therapies has primarily been limited to measuring changes in the amount of virus that can be detected in circulation.

Next Steps

As a result of Hemopurifier® + PR therapy outcomes, Aethlon has requested permission from the Medicity internal review board (IRB) to begin offering Hemopurifier® therapy to HCV-infected individuals that reside outside of India. The Company has also requested IRB permission to expand the treatment protocol to allow for up to seven Hemopurifier® treatments to be administered during the first week of PR drug therapy. Based on previous three-treatment protocol outcomes, Aethlon anticipates an expanded Hemopurifier® dosing schedule could establish new milestones for early undetectable viral load achievement. The Company also disclosed it will resubmit an investigational device exemption (IDE) which incorporates the Medicity data as part of its effort to gain FDA approval to initiate clinical programs in the U.S.

It is estimated that approximately 4 million Americans and 170 million people worldwide are infected with HCV, which leads to chronic liver disease or cirrhosis, and is the leading cause of liver transplant in the U.S. To date, almost 100 Hemopurifier® treatments have been administered in human studies. Previously, studies of the Hemopurifier® have been conducted at the Apollo, Fortis, and Sigma New Life hospitals in India. These studies demonstrated that Hemopurifier® therapy could safely reduce viral load in both HIV and HCV-infected dialysis patients without the administration of antiviral drug therapies. The Medicity study represents the first Hemopurifier® study in non-dialysis patients. In vitro studies have further validated the ability of the Hemopurifier® to capture a broad-spectrum of viral pathogens classified as bioterror or pandemic threats.

About Aethlon Medical

The Aethlon Medical mission is to create innovative medical devices that address unmet medical needs in cancer, infectious disease, and other life-threatening conditions. Our Aethlon ADAPT(TM) System is a revenue-stage technology platform that provides the basis for a new class of therapeutics that target the selective removal of disease enabling particles from the entire circulatory system. The Aethlon ADAPT(TM) product pipeline includes the Aethlon Hemopurifier® to address infectious disease and cancer; HER2osome(TM) to target HER2+ breast cancer, and a medical device being developed under a contract with DARPA that would reduce the incidence of sepsis in combat-injured soldiers and civilians. For more information, please visit www.aethlonmedical.com .

Certain statements herein may be forward-looking and involve risks and uncertainties. Such forward-looking statements involve assumptions, known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements of Aethlon Medical, Inc. to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. Such potential risks and uncertainties include, without limitation, that the FDA will not approve the initiation of the Company's clinical programs or provide market clearance of the company's products, future human studies of the Aethlon ADAPT(TM) system or the Aethlon Hemopurifier® as an adjunct therapy to improve patient responsiveness to established cancer therapies, the Company's ability to raise capital when needed, the Company's ability to complete the development of its planned products, the Company's ability to manufacture its products either internally or through outside companies and provide its services, the impact of government regulations, patent protection on the Company's proprietary technology, product liability exposure, uncertainty of market acceptance, competition, technological change, and other risk factors. In such instances, actual results could differ materially as a result of a variety of factors, including the risks associated with the effect of changing economic conditions and other risk factors detailed in the Company's Securities and Exchange Commission filings. These statements, including patient data, are based on information currently available to the Company's management and future patient results may differ from present results. The Company undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise.

Contacts:

James A. JoyceChairman and CEO858.459.7800 x301jj@aethlonmedical.com 

Jim FrakesChief Financial Officer858.459.7800 x300jfrakes@aethlonmedical.com

Marc Robins877.276.2467mr@aethlonmedical.com 

SOURCE Aethlon Medical, Inc.

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