American Foundation for AIDS Research, December 2004

As we approach 2005, the Insider asked leading scientists, clinicians, and activists what role they will play in the epidemic’s future.

What critical laboratory breakthrough do we need to overcome the virus?

John Rossi is professor and chair of the molecular biology department at the Beckman Research Institute, City of Hope, in Duarte, California.

There are two crucial unsolved problems in HIV research. First, how does HIV deplete CD4 helper cells? This is an immunological issue that involves how a cell responds when it contacts virus. If we could address the mechanism by which uninfected CD4 helper cells are killed, then we could treat HIV infection as a nonfatal, chronic illness. Secondly, how can we control the genetic variability of the virus — that is, the ability of the virus to radically mutate and still cause disease? We have several new clues about variability, including the involvement of cellular proteins such as the APOBEC family of cytosine deaminases (cell proteins that destroy foreign invaders). Once we can control HIV’s ability to mutate, we can rely on antiretroviral drugs to reduce replication and at least partially restore CD4 helper cells.

Julianna Lisziewicz is director of the Research Institute for Genetic and Human Therapy and president of Genetic Immunity in Washington, DC.

Clearly, antiretroviral therapy will not eradicate the virus. We need to train the immune system to overcome the virus. This has happened, but rarely. We should try to treat infection with immunization.

The discovery of immune correlates with virologic control is important, but such a discovery will not overcome the virus. We need to learn how to convert naive T cells into HIV-specific memory T cells in the presence of HIV-specific immune responses. This will teach us how to boost T cell responses with drugs, which might lead to a product that can be used for immunization.

Frederic Bushman is professor of microbiology at the University of Pennsylvania School of Medicine.

We need to understand more about how HIV grows in cells. New insight into a mechanism often suggests new drug targets. Once basic researchers devise new assays, usually the pharmaceutical industry quickly takes advantage by launching screens for new drugs. For example, in my lab, our gradual understanding of the HIV integration system helped identify integrase inhibitors. Thanks to many people’s work, several companies are now developing promising leads. Over the long term, this process should provide a steady stream of new treatments. HIV infection may never be cured, but I am hopeful that it will become easier to live with the disease.

Judy Lieberman is professor of pediatrics at Harvard Medical School and senior investigator at the Center for Blood Research.

From an immunologist’s perspective, HIV’s greatest mystery is what aspect of the virus-host cell interaction causes the immune system’s surveillance mechanism to fail. An effective vaccine is our most pressing need. Since the latest clinical results are discouraging, we must invest in as many different approaches — harnessing everything we learned from the past few decades of molecular biology and immunology research — to optimize the chances for success.

What is the most crucial issue facing people living with AIDS today, and how will it change in the upcoming years?

Mark Wainberg is professor and director of the McGill University AIDS Centre in Montreal.

The most important issue in therapy will be the durability of first-line regimens in both developed and developing countries, and whether important differences between these two settings will emerge.

Robert Murphy is professor of infectious diseases at Northwestern University, where he also serves as principal investigator of the AIDS Clinical Trials Unit.

The biggest question is, what is the safest, most effective antiretroviral regimen? Efficacy is relatively easy to determine, but clinical efficacy means more than just antiviral potency. It includes ease of administration, drug interaction, pharmacokinetics, resistance threshold, tolerability, and long-term toxicities. Long-term safety will ultimately drive future treatment decisions, as patients stay on therapy for decades.

Brian Gazzard founded the British HIV Association (BHIVA) and is currently consultant physician at Chelsea and Westminster Hospital in London.

Since the advent of highly active antiretroviral therapy in 1996, HIV infection has become an eminently treatable disease. Thus there has been a major shift from taking drugs at any personal cost to stay alive to living with a long-term disease while maintaining quality of life. There has been a tremendous switch from emphasizing a regimen’s potency to making treatments compatible with a normal lifestyle. Pill burden, frequency of administration, and freedom from irritating toxicities have become the main preoccupations of physicians, pharmaceutical companies, and individuals living with HIV infection. The major remaining concern is how to prevent the highly stigmatizing and potentially fatal complications of the fat redistribution syndrome.

Aside from access to drugs, what is the most important issue for activists in the next 5 to 10 years?

Active in HIV/AIDS advocacy work for 10 years, Tracy Swan is now coinfection project director at the Treatment Action Group in New York.

Coinfection with HIV and hepatitis C (HCV) presents a crucial set of issues for activists. HIV accelerates HCV disease progression. In the developed world, HCV-related end-stage liver disease has become a leading cause of death among people with HIV.

Addressing the needs of coinfected people reveals many gaps in HIV prevention, treatment, and research. Most coinfected people became infected through injection drug use. These infections are the legacy of the war on drugs and the inadequacies of addiction treatment. The ban on federal funding for syringe exchange programs ensures that injection drug users will continue to become coinfected. Prisoners are often coinfected and, outrageously, receive suboptimal HIV care and often resort to lawsuits to obtain HCV treatment. Coinfected people often have long histories of addiction, mental illness, poverty, homelessness, and incarceration. HIV programs are still struggling and sometimes failing to reach them. HIV and HCV are disproportionately prevalent among people of color, and their communities remain underserved.

In the coming years, the need for services, care, and treatment for coinfected people will grow as their resources shrink because of inadequately funded public health care infrastructure and out-of-control drug prices. We need multidisciplinary health care delivery systems to engage and support people through diagnosis, care, and treatment for HIV and HCV.

The US currently has no coinfection-specific care and treatment guidelines. Specialty care for HCV is not always available to coinfected people. Even when it is available, gastroenterologists and hepatologists are rarely knowledgeable about treating HIV. In turn, HIV clinicians must be educated about HCV transmission, diagnosis, and treatment.

The current HCV treatment, a combination of pegylated interferon and ribavirin, will not eradicate the virus for most coinfected people. Side effects and interactions with HIV drugs may be treatment limiting, or even life threatening. Until more effective, less toxic HCV treatments are available, we need research on treatment strategies. Although new therapies for HCV are in development, coinfected people have had to wait too long to obtain information about treatment safety and efficacy. So activists must continue to insist that HCV drugs be tested in coinfected people as soon as safety and activity are established.

Rachel Cohen is US director of the Campaign for Access to Essential Medicines at Doctors Without Borders (Médecins Sans Frontières) in New York.

Twenty-five years into the epidemic, 93% of HIV-positive people in developing countries still lack access to treatment. Worldwide activism forced governments and international institutions to confront the daily catastrophe of the AIDS pandemic, and medical action has proven the feasibility of antiretroviral therapy in resource-limited settings. Global initiatives are heavy on promises, but most institutions and governments continue to move at a snail’s pace, including donors in wealthy countries and national governments in heavily affected countries.

Antiretroviral therapy remains the only method of extending the lives of HIV-infected people. So the fight for access to treatment will continue and must remain a priority for AIDS activists throughout the world. But as treatment becomes more widely available, the challenges will change. Activists will need to broaden their focus from the “emergency response” mentality that is so necessary today to guaranteeing longer-term survival for HIV-positive people.

First, we must focus on clinical questions, including how to determine “when to switch” from first- to second-line regimens, how to manage the complexities of coinfections, how to develop diagnostic tools suitable for resource-limited settings, and how to design pediatric antiretroviral formulations.

Second, we should address political issues, such as guaranteeing predictable financing, ensuring that donor initiatives do not disrupt and undermine local efforts, securing political responsibility from national governments in developing countries, and ensuring that international trade rules regarding intellectual property do not threaten generic competition and a future supply of affordable medicines.

Third, we should identify concrete ways to support communities and individuals in mobilizing at the grassroots level to prepare for long-term, safe, effective antiretroviral therapy. This may entail supporting treatment “literacy” workshops and adherence support activities. Policy makers should meet with HIV-positive people to seek recommendations about the policies that affect their lives. We may need protest demonstrations to demand action and accountability from governments and international actors. AIDS must be wrestled from darkness and shame, as it was in parts of the US and such developing countries as South Africa, Brazil, and Thailand, and AIDS activism must embolden even the poorest and most vulnerable to refuse to die in silence and isolation.

But antiretroviral therapy must not lull us into forgetting that the therapeutic arsenal is far from adequate — drugs are still highly toxic, difficult to adhere to, and must be taken for life. So we must fight for universal access to a cure or a vaccine — even while fully acknowledging the extent to which scientific research has been outfoxed by the virus at every turn. Then, as expressed so exquisitely by Nelson Mandela in his 1994 inaugural address in reference to apartheid, “out of the experience of an extraordinary human disaster that lasted too long, [will] be born a society of which all humanity will be proud.”

Julie Davids is executive director and creator of Community HIV/AIDS Mobilization for Power (CHAMP) and a long-time member of ACT UP Philadelphia.

We must invest in a new generation of sustainable, diverse leadership — accountable to one another, armed with the skills to mobilize, and rooted in communities at the forefront of the HIV/AIDS struggle. A key issue is the sprawling, unaccountable, and inhumane prison system, which is at the core of the epidemic in the US, but at the periphery of our activist efforts.

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