Important note: Information in this article was accurate in July 2004. The state of the art may have changed since the publication date. 
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Project Inform Perspectives 38 - July 2004
Current anti-HIV drugs work at three points in HIV’s life cycle. Entry inhibitors, like enfuvirtide, keep HIV from entering cells. Reverse transcriptase inhibitors—like AZT, tenofovir and efavirenz—keep HIV from changing its genetic structure. Protease inhibitors, like atazanavir and Kaletra, ensure that newly made viral particles aren’t assembled into infectious virus. (For a list of these drugs and their classes, see the Drug ID Chart.)
After many years of research, drugs are nearing development that block another part of the viral life cycle. These are called integrase inhibitors. This article highlights both the challenges and the promise of integrase inhibitor development.
Viral integration is when newly made genetic material of the virus (called viral DNA) enters the nucleus of a cell and inserts itself into the cell’s genetic material (DNA). Once this integration is complete, the cell is operating on the genetic instructions of the virus as opposed to the cell and the cell becomes a sort of HIV factory. Integrase inhibitors seek to block the integrase enzyme from allowing this integration process from happening.
Blocking integrase could offer much to the treatment of HIV disease. Because it would work at a different part in the viral life cycle than existing drugs, an integrase inhibitor would likely work against virus resistant to the current drugs. Also, the integrase enzyme doesn’t occur naturally in the body, so blocking it might not cause some of the side effects common to the existing drugs.
Resistance to integrase inhibitors is likely to develop. However, researchers hope that integrase inhibitor resistant virus would be less able to infect other cells and make new virus. Such hopes have kept integrase inhibitor research alive despite the challenges involved in developing them.
Chemists must comb through millions of potential compounds when searching for drugs that may be active against HIV. In order to narrow the search, they must create tests that determine which candidates are most likely to be active. Creating tests that accurately mimic the integrase enzyme has been one of the biggest challenges. However, a number of private and government researchers have now developed tests for integrase, and two integrase inhibitor candidates have gone into human testing in the past two years.
The first, L-870,810 by Merck, was last reported on in the spring of 2003. It performed well in test tubes and in animal studies. In both test tubes and monkeys, resistance to L-870,810 was slow to develop and when it did, the resistant virus was severely crippled in its ability to reproduce. Initial tests in HIV-negative volunteers found that the drug was well tolerated. A phase II study was planned for 2003. Merck has been undergoing significant restructuring, however, and their HIV research has been slowed down considerably for the past year. They’ve stated recently that they are still committed to integrase research and we hope to hear more in the coming year.
The second integrase inhibitor candidate, S-1360, is a joint venture between Shionogi Pharmaceuticals and GlaxoSmithKline. S-1360 showed anti-HIV activity in test tubes and safety in animals. In phase I studies, volunteers maintained adequate levels of S-1360 in blood. This had been a concern before the study started, because the drug binds easily with blood proteins, keeping much of it from entering the cells where it needs to go. Side effects were minimal in the study and development moved forward.
A phase II study of S-1360 was conducted in early 2003 in HIV-positive people. Unfortunately, S-1360 did not reduce HIV levels enough to warrant continued development. The companies have a back-up candidate, however, currently called RSC 1838. This compound is similar to S-1360 in its structure and function. RSC 1838 has not yet entered human testing and few details of studies in test tubes and animals are available.
While it has taken longer for integrase inhibitors to make it into human testing than the current classes of drugs, the failure and/or delay of these first two is no reason to write off the entire class. People living with HIV stand only to gain from having more options in treating the disease, and determined activism has helped a number of other drugs make it to the marketplace.
Test tube studies of more than a dozen integrase inhibitor candidates have appeared in scientific journal articles over the past two years. Nearly all are the work of academic scientists in the United States and Europe. While it is too early to tell whether any of these will make it into development, it is imperative that activists work with researchers to help them overcome hurdles to drug development.
Several approved anti-HIV drugs originated from research started at universities. Drugs like enfuvirtide and tenofovir may never have made it through development without the assistance of community activists. Helping add integrase inhibitors to the list of approved drugs is merely one more challenge, and we are equal to the task.
In the lead article of PI Perspective #36, “The Cure: We Get What We Demand,” Project Inform announced changes in treatment and research advocacy priorities. Response to the issue was overwhelming and positive and many people wanted more information.
Project Inform’s treatment and research advocacy goals are to 1) Facilitate research toward a cure for AIDS; 2) Focus research on issues facing people with advanced stage HIV disease; 3) Address treatment access issues; 4) Address standard-of-care issues; and 5) Remain nimble and responsive to emerging information and issues.
Our strategies to meet these goals are varied and many. They include but are not limited to:
The following chart does not include all the issues that Project Inform is working on, but rather some representative examples of issues, how we address them and ways others can get involved.
Finally, another goal of this activist effort is to educate people about treatment activism and inspire people to become involved. To that end, in addition to periodic updates through Project Inform’s Treatment Action Network (TAN) at TAN@projectinform.org, articles focusing on various aspects of our treatment advocacy work will appear in PI Perspective throughout the year. Your input and involvement in the fight for a cure is always encouraged and welcomed.
| The issue | What we’ll do about it | How we’ll do it | What can others do? |
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| Potentially effective treatments and strategies often languish because researchers across disciplines rarely share data and ideas or think together strategically to solve problems. | Engage top HIV and other disease researchers in creating strategic plans for collaboration and the creation of new research studies. | Project Inform’s IRTT is an internationally acclaimed think tank, including thought leaders inside and outside the field of HIV to brainstorm on ways to repair the immune system of people with advanced stage disease. | Support Project Inform and/or individual research institutes. |
| Identify funding mechanisms for new research coming out of the strategic plans. Influence funding mechanisms toward research of interest to the community. | Foundation for AIDS and Immune Research (FAIR) has been instrumental in providing seed funding for many projects borne out of Project Inform-sponsored events on topics ranging from salvage therapy to STIs. Project Inform staff sits on the Board of Directors and the Scientific Advisory Board for FAIR as well as co-sponsors events with FAIR. The NIH funds the majority of HIV research worldwide. Most NIH research is conducted through the National Institutes of Allergy and Infectious Disease’s (NIAID) Division of AIDS (DAIDS). Project Inform meets with OAR and DAIDS staff to discuss priorities and work to influence funding decisions and programs in accordance with the needs of people with HIV. |
Donate to foundations that fund AIDS research, like FAIR. Supporting funding mechanisms like FAIR allows research to get off the ground quickly and move forward. |
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| Share ideas generated by the IRTT with research institutes like the Institute of Human Virology (IHV), individual researchers, other activists and PI constituents. | The IHV and the University of Baltimore is an integrated HIV research effort formed under the leadership of Dr. Robert Gallo. It is one example of the types of research efforts Project Inform engages in, through one-on-one interaction with researchers to providing input into scientific priorities of the institute. Creative, imaginative scientists working together hold the key to a cure. Maintaining relationships with the scientific community, fostering collaborations, providing community input into priorities and helping to remove barriers to moving innovative ideas forward are among the most important strategies activists can use to accelerate the pace of discovery toward a cure, outside of working to increase the resources for this effort. |
Serve on local Institutional Review Boards (IRBs) that review the ethics of research and the adequacy of informed consent documents. Get involved in local Community Advisory Boards (CABs) for HIV research centers. Educate yourself about new research opportunities and volunteer for studies that are meaningful and of interest to you. |
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| Large networks that establish scientific priorities and conduct research on therapy, basic understandings of HIV and vaccine research are inefficient and hinder progress toward a cure. | In 2004 proposals will be developed to “re-compete” nearly all of the large networks that conduct HIV research. Project Inform will influence the “re-competition” to serve the needs of our constituents. | Project Inform and other organizations attended preliminary meetings, hosted by DAIDS, on the re-competition issue. Several groups are following its progress and providing comment. Project Inform attended an inter-institute meeting debuting re-competition issues at NIH. This provided opportunity for Project Inform staff to hear concerns of other institutes as we formulate strategy. Project Inform will continue meeting with DAIDS leadership over the next year. The scope of influence involves assessing the structural needs of networks to support research toward a cure and making sure these needs are addressed in funding applications. |
Support Project Inform. |
| Potentially important therapies often face roadblocks in drug development. | Meet with pharmaceutical and biotech companies that have novel therapies to treat HIV to drug development plans and ensure they meet community needs and identify obstacles to progress and work to remove them. | As new therapy ideas are developed, Project Inform meets with industry sponsors in order to:
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Write or call your elected officials in Washington about the importance of funding biomedical research at the NIH and in particular the importance of HIV/AIDS research funding. |
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