It's Time to Approve More Surrogate Markers

The FDA is approaching a decision that will affect every person with HIV illness by deciding whether to use new surrogate markers to evaluate a therapy that might help restore the health of the immune system.

Across the country, drops in the death rate and clearing ofopportunistic infections have been reported, making many feel that we have turned the corner in this disease.

However, we do not know how long the human body can tolerate daily doses of heavy antiviral artillery. And we're not sure how to repair the damage already done by the virus to the immune system, or help the 20 to 30 percent of people who fail the drug therapies.

A major factor limiting the development of new kinds of therapies is the paucity of accepted markers for improved immune function. Only two markers have been widely accepted as connected to disease progression and mortality in a causal fashion: CD4 T-lymphocyte levels and the amount of viral RNA in the blood (viral load).

However, they are rather crude. They do not give a full picture of the health of the immune system. For example, many people want to know if using IL-2 will help them protect their CD4-cell repertoire or whether it might hasten "aging"of their cells. But viral load data tells us very little about either.

The great immunological event that underlies the efforts to develop therapies that boost the immune system is the observation that the immune system works well in controlling the virus for so long.

We know that after initial infection, the virus grows out of control, making perhaps tens of billions of copies per day for a period of time. Then the immune system, through a mechanism not fully understood, gets the viral burden down as much as seven logs -- better than any antiviral to date --and keeps it relatively low for many years. In the case of long-term non-progressors, the virus is kept under control for over 15 years. Even in the case of rapid progressors, the virus is usually contained for years. This powerful natural"antiviral" has never been identified, but over time it clearly weakens; in many ways it is the loss of this immune function that required we pay attention to HIV, and therefore led to the development of antivirals. After all, if the immune system kept the virus under control indefinitely, as it does so well for many years in the beginning, few of us would bother studying HIV because it would be a benign infection.

Some within the FDA recognize the need for the development of immune-based therapies, and the connection between this need and the evaluation of more surrogate markers. At a closed agency meeting to be held within the next few days, there will be a serious discussion of how to evaluate new therapies using immunological markers other than viral load and CD4 counts. It is clear that evaluating immune-based therapies cannot be done using markers designed to measure the effectiveness of antivirals.

There are a number of candidate immunological markers which seem highly correlated with disease progression, such aslymphocyte proliferation to antigens (the body's readiness to produce large numbers of cells to fight an illness when presented with pieces of the enemy pathogen), elevated levels of cytokines like gamma interferon, RANTES, MIP-1-alpha, and MIP-1-beta (substances that fight viruses that are secreted by cells when they are presented with the virus -- see "CD8 Cells: Suppressive Factors Discovered," AIDS Treatment News #238, January 5, 1996), DTH (delayed type hypersensitivity reactions, a test of the body's ability to fight an array of common illnesses that we have been vaccinated against or which we have been exposed to, like measles or polio, or HIV itself) and many others.

There are data that lead us to believe that effective immune-based therapies are possible with refinement of existing efforts. For example, ACTG 315 is a recent study which shows that roughly one third of people with moderately advanced disease (a CD4 count of 100-300) on antiviral therapy have a partial return of non-HIV-specific lymphocyte proliferation to some recall antigens, and enhanced levels of both memory and naive CD4-cells and naive CD8 cells. These findings lead one to hope immune-based therapies that restore these markers might help the body fight the damage done by the disease. But no markers have been accepted by the FDA for immune restoration, so the likelihood that the therapies will be rapidly developed is minimal.

It has been known for some time that non-progressors have quite powerful HIV-specific immune responses which people who progress lack, such as lymphocyte proliferation and enhanced levels of chemokines such as RANTES and MIP-1-alpha and beta. We already have therapies which partially restore some HIV-specific responses, such as the Salk vaccine, but the existing crude markers cannot tell us their value without unrealistically large, long, and expensive trials.

While antivirals can block viral replication, it is unclear that they can strengthen the immune system's capacity to fight the virus. If a therapy can strengthen the body's ability to control the virus after antivirals have reduced the viral load, perhaps we could stop using antivirals for long periods of time. This would lengthen the usefulness ofthe drugs and improve people's quality of life. For example,if IL-2 followed by revaccination could restore the body's ability to fight diseases, it would greatly benefit those who must constantly use prophylactic regimens, not withstanding antiviral therapy.

But we'll never know without FDA recognition of new markers, because the two now used tend to weed out any efforts except the refinement of antivirals.

The FDA needs to send a signal that it will look at new surrogate markers. In addition to its meeting next week, at which a discussion on surrogate markers to evaluate a particular immune-based therapy will occur, it should convene a joint session of its antiviral drug advisory committee and its biologic response modification advisory committee in a public session to identify those immunological markers which indicate improved health.

Convening these public bodies would send a signal to public and private bodies that would speed research and development of immune-based therapies.