New HIV Cure Research Released Today at the XIX International AIDS Conference (AIDS 2012)

Thursday, 26 July, 2012 (Washington D.C, US) - A new study has been released at the XIX International AIDS Conference (AIDS 2012) in Washington today confirming that patients treated early and then taken off antiretroviral therapy have shown no signs of a resurgence of their HIV infection.

There exists a unique cohort of patients in France who became HIV infected, started therapy early, and were able to successfully stop therapy without having a resurgence of their HIV infection (the "Visconti Cohort"). The study confirms the benefits of treating HIV at the very early stages of infection.

"Six years after interruption of treatment, patients treated early on in the post-infection period present a perfect ability to control the HIV infection. The patients in the ANRS EP47 VISCONTI cohort possess an extremely low "reservoir" of HIV in the cells at a similar level to that of "HIV controller" patients.

"These results suggest that the antiretroviral treatment should be started very early after infection, said Charline Bacchus, lead researcher of the study at the French National Agency for Research on AIDS and Viral Hepatitis (ANRS):

There is an immensely valuable store of knowledge to be gained from analyzing the immunological characteristics that made therapy redundant for these patients and the VISCONTI group of patients is one of the key scientific reasons behind the renwed optimism in the search for an HIV Cure.

Another study was presented today at AIDS 2012 by Daniel Kuritzkes. They studied the persistence of HIV in two HIV-infected men who underwent allogeneic (foreign) stem cell transplantation for treatment of lymphoma. Both patients had been infected for many years, and had been on antiretroviral therapy that completely suppressed HIV replication, but continued to have detectable latent virus in their circulating lymphocytes prior to transplantation.

The patients received a milder form of chemotherapy (the "conditioning" regimen) prior to transplant, which allowed them to stay on their HIV medications throughout the transplant period. Although HIV was detectable in their cells immediately after transplant, over time the transplanted donor cells replaced the patients' own lymphocytes.

As this occurred, the amount of HIV DNA detectable in the patients' blood cells decreased and became undetectable. One patient has now been followed for nearly two years since his transplant and the other for three-and-a-half years. No traces of virus could be found in the patients' plasma, nor were we able to recover virus from the patients' CD4+ T-cells by a sensitive culture method. In addition, we observed a significant decline in HIV antibody levels (tests conducted by Dr. Michael Busch in San Francisco), providing additional evidence for a lack of ongoing exposure to HIV antigen.

In contrast to the "Berlin" patient, who received cells that were intrinsically resistant to HIV infection because they lacked a key HIV receptor (the CCR5 receptor), the cells our patients received were CCR5+. We believe that continuous administration of effective antiretroviral therapy protected the donor cells from becoming HIV infected as they eliminated and replaced the patients' immune cells, effectively clearing the virus from the patients' blood lymphocytes. Tissue sampling and analytic treatment interruption are needed to assess fully the extent of HIV-1 reservoir reduction following allogeneic stem cell transplantation.

Results from a study led by David Margolis at the University of North Carolina at Chapel Hill were also published this week in Nature. Margolis and his team showed that a dose of a drug that inhibits an enzyme involved in HIV silencing leads to rapid production of HIV RNA in the patient's latently infected cells. This could make such previously unreachable viral reservoirs susceptible to curative strategies. For example, in combination with treatments that enhance host immune defense, unmasking latent virus might allow clearance of infection.

Last week the Inaugural Global Scientific Strategy Towards an HIV Cure was launched amid renewed optimism from the world´s leading HIV/AIDS scientists that the future prospects for finding an HIV cure are increasing.

Over the past two years the International AIDS Society (IAS) has convened a group of international experts to develop a roadmap for research towards an HIV cure. Published online in an abridged form last week in Nature Reviews Immunology, Towards an HIV Cure identifies seven important priority areas for basic, translational and clinical research and maps out a path for future research collaboration and funding opportunities.(1)

"The strategy is the result of a collaborative effort which has produced a roadmap that will constructively move HIV Cure research forward," said Françoise Barré-Sinoussi, the co-discoverer of HIV, Director of the Regulation of Retroviral Infections Unit at the Institut Pasteur in Paris and the IAS President-Elect. Barré-Sinoussi, together with Professor Steven Deeks, Professor of Medicine at the University of California, San Francisco, is co-chair of the group of 34 leading HIV scientists and clinicians who have developed the Global Scientific Strategy. Professor Barré-Sinoussi and Professor Deeks states the case for HIV cure research in a commentary piece published last week in Nature. (2)

"The science has been telling us for some time now that achieving a cure for HIV infection could be a realistic possibility. The time is right to take the opportunity to try and develop an HIV cure - we might regret never having tried", concluded Barré- Sinoussi at the D.C. launch.

The vision for the IAS strategy for an HIV cure is very clear: a safe, affordable and scalable cure will improve the health and quality-of-life for those with established infection, reduce the risk of transmission of virus to those not infected, and ultimately allow resources to be shifted to other needs.

Some 300 scientists attended a two day HIV Cure symposium prior to AIDS 2012 and the International AIDS Society today announced that the next Towards an HIV Cure pre-conference symposium will be held in Kuala Lumpur on June 28 & 29 in 2013 ahead of the 7TH IAS Conference on HIV Pathogenesis, Treatment and Prevention (30 June- 3 July 2013 | Kuala Lumpur, Malaysia)

Major investments in science have resulted in the worldwide availability of over 20 anti- HIV drugs. When used in combination, these drugs restore health, prolong life and reduce transmission of the virus. HIV-infected individuals who harbour drug-susceptible virus, who have access to antiretroviral drugs, who can tolerate the drug side effects, toxicities, and other complications, and who are able to adhere to therapy can maintain control of HIV infection indefinitely.

Despite these successes, these therapies have limitations. They do not eradicate HIV, requiring people to remain on expensive and potentially toxic drugs for life. They do not fully restore health as patients still experience co-morbidities such as increased cardiovascular disease, bone disorders or cognitive impairment. They are expensive and difficult to deliver to all in need.

Although the cost of delivering antiretroviral drugs to the more than 34 million people now living with HIV has decreased substantially, and the availability of these drugs in resource-poor settings has steadily increased, the costs associated with delivering antiretroviral drugs is overwhelming many organizations and public health systems. Estimates put the cost of the funding response to the HIV/AIDS epidemic by 2015 between US$22-24 billion per year (3) and between US$19-35 billion per year by 2031, with antiretroviral treatment accounting for up to 70 per cent of the total cost of care in the most affected countries. (4)

It is estimated that for every person starting treatment, two are newly infected, a path that is clearly unsustainable.

Given these limitations, there is growing recognition that the search for an HIV Cure is an imperative both in terms of the individual and public health benefits it would provide and also an opportunity to potentially avoid the long-term cumulative costs of ART. (5)

Also, an effective and scalable HIV cure will likely achieve what preventative approaches aim to do, which is to essentially stop transmission of HIV to those who are uninfected and restore the immunological function and normal health to those who are infected (6).

The renewed optimism in the search for an HIV Cure amongst scientists is based on a number of scientific advances that are helping to shed light on why it is that HIV remains persistent.

Scientists have known for some time now that latent HIV reservoirs, where HIV hides and persists, are one of the main barriers to finding a cure. This is precisely why treatment does not eradicate HIV and why, when treatment is stopped, the virus rebounds.

"What we haven't had until very recently is clear insights into why HIV persists during therapy," said Steven Deeks, at the launch in Washington D.C. "Our basic understanding of the mechanisms of HIV persistence in latent reservoirs is far superior than it was a decade ago. We are entering a stage in the epidemic in which we can seriously begin testing drugs that either prevent latency or which force the virus out of its hiding place, make it susceptible to our current drugs." (7)

Why is an HIV Cure feasible?

Several recent observations make scientists enthusiastic about pursuing cure research.

For the first time ever there is now a "proof of concept," as scientists like to call it, for an effective cure. The case of Timothy Brown, the so-called "Berlin Patient", who received a stem-cell bone-marrow transplant in 2007 and is now considered to be cured of HIV, has proved that a cure is at least possible. This stem cell transplant worked because the donor was among the one percent of Northern Europeans who lack CCR5, the "doorway" through which HIV enters cells. While it is unrealistic to pursue this risky and costly therapeutic approach for most people, it has nevertheless got scientists thinking about the use of gene therapy to modify a patient's own immune cells to make them resistant to HIV infection.(8)

The molecular biology regarding how HIV DNA becomes integrated in the chromosomes of infected people is the focus of intense research. This work has already led to a number of possible interventions, some of which are being tested in the clinic. Recently, in a test in HIV+ patients, David Margolis and colleagues showed that a dose of a drug that inhibits an enzyme involved in HIV silencing leads to rapid production of HIV RNA in the patient's latently infected cells. This could make such previously unreachable viral reservoirs susceptible to curative strategies. For example, in combination with treatments that enhance host immune defense, unmasking latent virus might allow clearance of infection (9).

Scientists have also been aware of a rare group of HIV infected people who appear to have naturally "cured" their own infection. These "elite controllers" are HIV positive but have no readily apparent virus in the blood. Scientists are gaining a better understanding of this group of patients.

There exists a unique cohort of patients in France who became HIV infected, started therapy early, and were able to successfully stop therapy without viral rebound (the "Visconti Cohort"). The study confirms the benefits of treating HIV at the very early stages of infection. There is an immensely valuable store of knowledge to be gained from analyzing the immunological characteristics that made therapy redundant for these patients. (10)

Understanding this group of people who efficiently control the virus replication and reservoirs, scientists believe, might lead to novel therapeutic interventions.

How can HIV be cured?

Currently, the following strategies are being investigated and it is expected that all of these strategies will be more efficient in combination with each other, alongside the use of antiretroviral therapy to at least protect the immune system of patients to prepare them for a cure:

• Gene therapy
• Treatment Optimization and Intensification (eliminate all replication)
• Reversal of HIV latency  (increase virus production)
• Immune-based Therapies (reverse pro-latency signaling)
• Therapeutic Vaccination (to enhance host-control)

What are the HIV Cure research priorities?

The Global Scientific Strategy Towards an HIV Cure identifies and recommends seven key priority research areas, as outlined in the table below.

Funding and collaboration

The IAS and its partners will foster international research collaborations for an HIV cure and monitor progress made in the roll-out of the scientific strategy.

Addressing the scientific barriers will require substantial resources. NIH recently awarded the Martin Delaney Collaboratories, large grants for research toward a cure, as well as a series of targeted funding initiatives to support this area of research. These programs are in addition to the substantial portfolio of ongoing basic and clinical HIV research of research related to the elimination of viral reservoirs and other research toward a cure.

Other traditional government-based funders of biomedical research like the French National Agency for Research on AIDS and viral hepatitis (ANRS), the Canadian Institutes of Health Research (CIHR) and the Medical Research Council (MRC) in the United Kingdom are also increasing their commitment to cure research, and a number of non-government groups are raising and spending considerable amounts of money on cure research. Many of the pharmaceutical companies that invested heavily in antiretroviral drugs are now also allocating some of their resources to address this question.

The investment now going to cure research is substantial but almost certainly not sufficient. It is hoped that some of the emerging economies among countries heavily affected by the epidemic will take some ownership of this agenda.

"Under no circumstances should the inclusion of "cure" in the global response direct funding away from treatment, prevention and care programmes, or from biomedical research on HIV and its consequences, including vaccine and other prevention research," said Barré-Sinoussi. "However, it is imperative that donors, governments and the AIDS community make viable economic investment in HIV cure research, and right now."

Development and funding of a scientific agenda are needed but they are not sufficient. The Global Scientific Strategy Towards an HIV Cure has identified six key steps that need to be taken to enhance progress in HIV Cure research.

• The establishment of large, multinational collaborations involving experts from multiple disciplines (including those outside of the HIV arena) will likely be needed. The NIH-funded Martin Delaney Collaboratories were a first step in this direction;
   
• Translational research involving teams of basic and clinical scientists working side-by-side with knowledge flowing in both directions are needed;
   
• The optimization of relevant animal models for discovering and testing novel interventions is needed. The development of effective antiretroviral treatment for SIV in macaques has only recently been achieved; it is expected that this model will prove to be very important for future discovery when studies cannot be safely conducted in humans;
   
• Young researchers need to be mentored and supported, as they are likely to be the source of innovative, out-of-the-box thinking;
   
• The profound regulatory issues that surround the testing of novel drugs (many with high potential for toxicities) in a population that is generally doing well will need to be addressed, and a regulatory pathway for advancing candidate therapies through the clinical trial process identified;
   
• Strong community support is needed to advocate against complacency and to ensure that patients and their communities are fully engaged and informed about the risks and benefits of curative studies.

END

Notes to Editors
1. See:
a. The International AIDS Society Scientific Working Group on HIV Cure. Towards an HIV cure: A Global Scientific Strategy, Nature Reviews Immunology, 20 July 2012, pp1-8(doi: 10.1038/nri.3262) http://www.nature.com/nri/index.html

b. The International AIDS Society Scientific Working Group on HIV Cure, Towards an HIV Cure : A Global Scientific Strategy, Full Recommendations Report”, July 19, 2012, www.iasociety.org

2. Françoise Barré-Sinoussi & Steven Deeks, Towards an HIV Cure, Nature, July 18, 2012, pp 293-294

3. WHO, UNICEF, and UNAIDS, Global HIV/AIDS Response 2011, p9

4. aids2031 Initiative, Aids: Taking a Long Term View, February 2011, p2

5. See :
a. Richman, D.D., et al. The challenge of finding a cure for HIV infection. Science 323, 1304-1307 (2009).

b. Trono, D., Van Lint, C., Rouzioux, C., Verdin, E., Barre-Sinoussi, F., Chun, T.
W., and Chomont, N. 2010. HIV persistence and the prospect of long-term
drug-free remissions for HIV-infected individuals. Science 329(5988): 174-80.

c. Cohen, J. The emerging race to cure HIV infections. Science 332, 784-785,
787-789 (2011).
6. Françoise Barré-Sinoussi & Steven Deeks, Towards an HIV Cure, Nature, July 18, 2012,pp 293-294

7. Current HIV Cure clinical trials engaged in safely eliminating latent infection in individuals on antiretroviral therapy. See The International AIDS Society Scientific Working Group on HIV Cure, Towards an HIV Cure : A Global Scientific Strategy,
Full Recommendations Report, July 19, 2012, p.51, www.iasociety.org,

8. The International AIDS Society Scientific Working Group on HIV Cure. Towards an HIV cure: A Global Scientific Strategy, Nature Reviews Immunology, 20 July 2012, pp 18 (doi: 10.1038/nri.3262)

9. Archin NM, Vaidya NK, Kuruc JD, Liberty AL, Wiegand A, Kearney MF, Cohen MS, Coffin JM, Bosch RJ, Gay CL, Eron JJ, Margolis DM, Perelson AS. Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection, Proceedings of the National Academy of Sciences, USA. 2012;109(24):9523-8. PMID:22645358

10. Hocqueloux, L., Prazuck, T., Avettand-Fenoel, V., Lafeuillade, A., Cardon, B., Viard, J. P., and Rouzioux, C. 2010. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. AIDS 24(10): 1598-601.

Further Information:

Michael Kessler
IAS International Media Consultant
michael.kessler@aids2012.org
Mob:+1 202 430 2160
Skype: micgkpi
www.iasociety.org

About the IAS

The International AIDS Society (IAS) is the world's leading independent association of HIV professionals, with over 16,000 members from more than 196 countries working at all levels of the global response to HIV. Our members include researchers from all disciplines, clinicians, public health and community practitioners on the frontlines of the epidemic, as well as policy and programme planners. The IAS is the custodian of the biennial International AIDS Conference, which will be held in Washington, D.C., in July 2012, and lead organizer of the IAS Conference on HIV Pathogenesis, Treatment and Prevention.
www.iasociety.org | www.aids2012.org

About the Towards an HIV Cure Global Alliance

The Initiative "Towards an HIV Cure" began in February 2011 with the creation of the International Scientific Working Group charged with the responsibility of developing a Global Scientific Strategy. The group is composed of 34 basic scientists and clinicians from around the world working in cooperation with a stakeholders' advisory board composed of community advocates, major research agencies and foundations as well as researchers from low-and middle income countries. The full list of members is available on the IAS website.

Consultations on the draft strategy were held in Autumn 2011 with scientists from various disciplines, patient organizations, industry, international organizations, and regulatory and research funding agencies.

Following the launch of the Strategy, the IAS and the Advisory Board Towards an HIV Cure will work together to facilitate the roll-out of the scientific strategy, by carrying out further research on ethical issues linked to HIV cure research and the cost-effectiveness of HIV cure strategies. It will also facilitate information and research data exchange on an HIV cure, stimulating innovative public-private research collaboration efforts within the Industry Collaboration Group (ICG), as well as developing policy and advocacy activities aimed at fostering research.

About ANRS

The Anrs is the French National Agency for Research on AIDS and Viral Hepatitis, an autonomous research Agency at Inserm. Its mission is to seek new ways to improve the prevention and treatment of these infections, both in the developed world and in resource limited countries. The Anrs brings together researchers and physicians from all disciplines (basic science, clinical research, public health, economics and  prevention). At its  research sites in Sub-Saharan Africa and in South East Asia, the Anrs mobilizes French and local scientists to collaborate on healthcare issues of paramount importance to these settings. The French ministries of research and health allocate to the Anrs an annual budget of approximately 45 million Euros. In 2011, ANRS devoted 5.6 million euros to cure-related fundamental and clinical research programs.

About Sidaction

Sidaction, a France-based NGO, is a diverse coalition of individuals and organizations from France and from developing countries. Dedicated to fundraising, advocacy, and technical assistance to fight HIV/AIDS in France and in 32 low and middle income countries, Sidaction raises private funds to promote cutting-edge scientific research and to improve access to prevention, care, treatment, and support programs.

About TAG

The Treatment Action Group (TAG) is an independent AIDS research and policy think tank fighting for better treatment, a vaccine, and a cure for AIDS. TAG works to ensure that all people with HIV receive lifesaving treatment, care, and information. www.treatmentactiongroup.org

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