Novel Targets: The Need for Novel Targets and Approaches to HIV Therapy
The stupidest virus is cleverer than the cleverest virologist.
For several years now antiretroviral therapies have been the means by which many HIV-infected persons have managed to stave off disease and death. Yet despite the apparent success of antiretrovirals, their use as the sole therapeutic approach to HIV disease has many limitations. The most glaring of these limitations is, of course, access. Antiretrovirals are only useful for patients who can access them either through insurance, government subsidy, or some other means. This leaves out a vast majority of the world's HIV-infected population.
Even if economics and access were not an issue, experience using these drugs has taught us that adherence can be extremely problematic for many patients. Patients do not adhere to antiretrovirals for a number of reasons including negligence, forgetfulness, and intolerance of side effects; but in the end, the reason for failure, more often than not, is resistance. Some studies show that as much as 70 percent of patients fail their first antiretroviral regimen within 48 weeks. Given that all our current antiretrovirals harbor the "Achilles heel" of resistance, our only hope for the long-term success of these drugs is that drug development will outpace the incidence of resistance. This seems unlikely.
Pharmaceutical companies are making efforts to simplify dosing regimens, to improve side effects profiles, and to find ways to improve adherence. Under pressure from AIDS advocates, a few companies have even begun to talk about lowering costs of drugs.
Still, even if we could overcome all these limitations, we are left with the fact that long-term use of antiretrovirals is increasingly being associated with the emergence of debilitating toxicities. Given the problems of access, adherence, costs, toxicities, etc., it seems unlikely that antiretrovirals will ever be an effective solution for the worldwide AIDS epidemic.
This is not to say that antiretrovirals have not been an advance in HIV therapeutics. Many of us would not be here but for their existence. But in the larger scheme of things, antiretrovirals have not turned out to be the long-term solution to a pandemic that threatens to destabilize governments and wreak havoc on large segments of the world's population. For this reason many scientists, healthcare providers, consumers, and advocates have begun searching for different approaches to the treatment of HIV disease.
What will it take to develop new targets for therapy and new approaches to HIV/AIDS? The short answer is that finding a different approach may require a lot more basic understanding of the science of HIV. Unless science serendipitously stumbles upon some solution, researchers likely will not be able to develop new approaches to HIV therapeutics without learning much more about how the virus works and how our immune system functions -- not just in response to the virus, but under normal circumstances.
There have been many advances in our knowledge of viral dynamics and pathogenesis in the past few years. Yet, despite this knowledge, to date all our current drugs interfere only at 2 points in the viral lifecycle: during reverse transcription and protease processing. The research community is just now working on new targets such as virus-cell fusion (e.g., pentafuside), coreceptor attachment (e.g., SCH C & D), and integration (e.g., Shionogi's S-1360 and Merck's integrase inhibitor in early development). To exploit the remaining potential targets we must do a better job of characterizing viral and immunological processes. We need a better understanding of integration, replication, assembly, budding, etc. (as well as the immune system's response to these viral activities) before we can develop new compounds or approaches to interfere with these processes. We need to understand virulence, infectivity, and pathogenicity to further refine treatment and care.
What then are the ideal characteristics necessary for new therapeutic approaches? Given that the vast majority of HIV-infected patients live in underdeveloped countries, it is clear that a successful HIV therapy must not only be affordable and easy to administrate, but must provide lasting and meaningful benefit. Current antiretrovirals simply do not fulfill these requirements. Currently approved therapies are plagued by issues of viral resistance, questionable pharmacokinetics, and insufficient potency. As a result, these drugs do not sufficiently penetrate cellular and anatomical reservoirs, do not fully restore immune function, and allow for persistence of the viral infection.
Given the nature of HIV -- its high mutation rate, its tendency to preferentially infect HIV-specific CD4 T cells, and its ability to persist in memory cells -- it seems unlikely that antiretrovirals alone will ever be sufficient to provide effective long-term control of this viral infection. In addition, while a virologic approach to treating HIV infection may directly affect the virus, in some instances it does not restore (or only partially restores) immune function. For this reason many in the research community have begun to think of alternate approaches in terms of immune-based or gene-based therapies.
At the top of the wish list of immune-based therapies is the development of a therapeutic vaccine. The strategy of a therapeutic vaccine is to prompt the body's own immune system to recognize, respond to, and control HIV. Some of the most promising approaches among therapeutic vaccines prompt cytotoxic T lymphocytes to control HIV infection. Some "prime-boost" strategies have shown the ability to bring down viral loads and avoid CD4 T cell loss in animal models. Hopefully these results will translate to humans in the near future. Still, even in the best of circumstances, these vaccines do not eliminate infection and the loss of immunological control in the future may be a distinct possibility. The virus of at least one animal has been able to evolve out from under the immunological control elicited through a therapeutic vaccine.
Vaccine development certainly has gotten the most press coverage, but other immune-based therapies are currently under investigation. Among these are cytokines, cytokine modulators, active and passive immunotherapeutics, ex vivo expansion and re-infusion of antibodies and T cells, bone marrow manipulation, and the use of stem cells.
The biggest challenge in developing immune-based therapies is that the methods of evaluating immune function are not always well defined (see "Immune-Based Therapy" in this issue). With the use of antiretrovirals, one simply measures viral load to gauge effectiveness. Because of our limited knowledge of the immune system, it is not always clear what correlates of immune protection should be measured. In particular it has been difficult to evaluate immune-based therapies when they are used in the context of antiretroviral therapy.
Often as advocates and activists we get caught up in the latest data on a new compound -- its different resistance profile, its increase in potency, its new simplified dosing. All these incremental improvements are important for those of us who have the luxury of access to these drugs. However, we must not forget that for the population at-large much work still lies ahead in providing a meaningful solution to HIV disease. Novel approaches may provide their only true hope of living productive, healthy lives.
This article was provided by The Center for AIDS. It is a part of the publication Research Initiative/Treatment Action!. Visit CFA's website to find out more about their activities and publications.