At this point the viral enzyme called reverse transcriptase, which is usually not found in normal cells, induces the production of a complementary viral DNA.

Antiviral agents have been found which will inhibit the action of this enzyme. The various viral components are then assembled at the host cell membrane and virus buds off. Inhibitors for each of these major steps could theoretically be developed. Available drugs that have been shown to inhibit some of these processes have been and are being examined for both in vitro, and in vivo, efficacy.

In the search for antiviral agents against HTLV-III, several working assumptions have been formulated from basic research. I have included the seven in my written testimony, but will only mention the last one in my oral testimony.

HTLV-III has a capacity that is characteristic of retroviruses as a general class. It can become incorporated into the genetic material of the host, with a potential for reactivation at a later time. Thus, experimental strategies must take into consideration the possibility that prolonged treatment and observation of the patients will be necessary.

A word about a screening approach to antiviral agents.

In addition to the targeted approach to antiviral agent development, a more rapid approach, that is, screening existing compounds, is under way, supported by both Government and industry. Various rapid screening systems used by the NCI involve the use of a special cell line-given the code name H9-that permits HTLVIII to replicate without killing the cell line.

The capacity of the virus to replicate is reflected in the production of certain viral products that can be readily quantitated.

If a given agent shows an antiviral potential, it is quickly studied to determine whether certain modifications in the chemical makeup of the compound increase or decrease antiviral effects. Within the last 9 months, the Clinical Oncology Program, NCI, has screened over 100 drugs and has identified potent agents that inhibit the virus at doses that do not kill normal T cells or substantially damage their normal immune reactivities. One of these-suramin-is now in extensive clinical testing. Another promising compound is a proprietary agent. We are making progress in this area. The chart shows an overview of some of those agents under current study.

There are a number of antiviral agents already identified with clinical potential and the status of these agents is summarized in our written testimony. I will just touch on one or two in areas which are particularly significant.

Particular attention has been given to the development of suramin as an experimental antiviral agent in AIDS because it illustrates the effective collaborative potential of the intramural and extramural institutions to rapidly test promising agents detected in the drug screening systems described earlier. After the demonstration that HTLV-III was the etiologic agent of AIDS and the development of drug-screening systems in May 1984, suramin was selected by investigators within the NCI for testing, because of its reported ability to inactivate reverse transcriptase.

The drug was found to be a potent inhibitor of HTLV-III replication, and the cell-killing caused by this replication, in vitro. Since

this drug had been used in human beings for decades as an antiparasitic agent, data were available on acceptable dose regimens and information on its known toxicity in humans had been described. These factors allowed us to bring the drug to trial very rapidly.

A pilot feasibility/safety trial using this drug in patients with AIDS was initiated by NČI at the NIH Clinical Center in August 1984. In addition, other investigators, both in this country and abroad, were encouraged to consider this agent, and a meeting of interested investigators was organized to exchange information.

In the spring 1985, clinical investigators from seven geographically separated institutions initiated experimental therapy trials using this agent under an investigational new drug application [IND], sponsored by the Cancer Therapy Evaluation Program of the NCI. A collaborative phase I study was thus initiated.

Throughout these studies there has been a flow of information in both directions between intramural and extramural investigators, permitting a fine-tuning and adjustment of the experimental regimens. The results to date suggest that one can, indeed, suppress replication of the HTLV-III virus, providing that one maintains a threshold level, approximately 100 micrograms/ml, of the drug in the patient's bloodstream. Although promising and in need of expanded studies, suramin, as a single agent, has not provided definite clinical benefit to the patient.

Ribavirin is a broad spectrum virustatic agent with a ribonucleoside structure. It is currently under study as well. I will not describe the activities of alpha-interferon.

A word about HPA-23. HPA-23 has been shown to inhibit reverse trascriptase and is currently under study in Europe. French investigators have reported that this drug was able to suppress virus recovery in patients while on treatment but the virus reappeared after therapy was stopped. No clinical improvement was seen in these patients. Its use has been associated with low platelet counts which may preclude extensive use of this agent; nevertheless, we are awaiting the submission of appropriate drug manufacturing and testing information to the FDA by the developer in order to initiate a clinical study with this agent in the United States.

Another drug, foscarnet-phosphonoformate an antiviral first identified for its antiherpes activity also inhibits reverse transcriptase. This agent, developed in Sweden, has entered clinical trials in Europe and is scheduled for clinical trials in this country.

Monoclonal antibodies are on our list of efforts.

Let me move to another chart. It illustrates a central part of the immune system.

The immune systems of patients with AIDS are damaged due to the destruction of helper/inducer T lymphocytes by HTLV-III. These are the cells which are responsible for the initiation and regulation of virtually all immune functions of the human body. Following stimulation by a foreign substance, this cell regulates the activation of the B lymphocyte which is responsible for antibody production, other T lymphocytes which are responsible for the killing of viruses and tumor cells, and monocytes which are responsible for killing a wide variety of foreign substances including para

sites and bacteria. Many of the activities of the helper/inducer T cell are carried out through the soluble protein messengers, interleukin-2 and gamma interferon. It is this central component of the immune system, the T4 lymphocyte, which is attacked and destroyed by the AIDS retrovirus. While much has been learned in the area of the basic science of AIDS, there remains no effective therapy for the profound immune defects these patients develop.

Therapeutic strategies designed to enhance immune functioning in patients with AIDS have concentrated on three basic areas: one, the wholescale replacement of the immune system; two, enhancement of the remaining immune system; and three, as just discussed, inactivation of the retrovirus responsible for the progressive destruction of the immune system.

A wide variety of substances are available which have the ability to modify in the test tube the human immune response. Among these are biologic substances such as interleukin-2 [IL-2], the interferons, the thymic hormones and a variety of synthetic chemical substances. I will not mention each one of these individually, but they are in our written testimony.

A word about isoprinosine. This is a derivative of the nucleoside inosine which is a derivative of the DNA base adenosine. Partially through funding provided by an NIAID cooperative agreement, this compound was studied in a group of patients with AIDS and related illnesses at St. Luke's-Roosevelt Hospital in New York. These studies failed to reveal any clinical efficacy of the drug in the treatment of AIDS and had minimal effects on the immune function of patients with other less severe HTLV-III related illnesses.

Combination therapy. No single agent or therapeutic modality as yet seems capable of substantially altering the overall clinical course of the patient with AIDS. The role of antiviral drugs as single agents in patients with prodromal forms of AIDS has not been explored, but it may soon be possible to do so. Although drugs are currently available which have the ability to decrease viral shedding; and drugs and technologies, such as bone marrow transplantation, can somewhat improve the immune function of these patients, treatment with individual modalities thus far falls short of the desired mark.

Therefore, in addition to current projects studying single agents, several efforts are under way in the area of combination therapy involving immunotherapy and antiviral drugs.

I will not spend time describing the treatment of the infectious and neoplastic complications of AIDS. That is not really the focus of this hearing, although it is an important aspect of caring for the AIDS patient.

A word about making drugs available for patients.

In order for clinical testing to proceed with products intended for use in the treatment of AIDS, or any other condition, an IND application is filed with FDA. The IND must contain information needed to demonstrate the safety of proceeding to test the drug in human subjects, including drug composition, manufacturing and control data, results of animal testing, training and experience of investigators, and a plan for clinical investigation. In addition, assurance of informed consent and protection of the rights and safety of human subjects is required.

The FDA has been extremely sensitive to the gravity of the AIDS problem and has expedited all requests for the study of experimental agents for this condition. The FDA has met on one or more occasions with every manufacturer who has expressed an interest in submitting an IND for the use of a product in AIDS or AIDS-related complex to discuss the procedures for filing an IND.

In these meetings with company officials, FDA scientists have discussed the information necessary to submit for inclusion in the IND request. They have also assisted in the design of the clinical plan so that studies on drugs which might prove to be useful therapeutic modalities for AIDS could be initiated rapidly once the IND is filed.

Of these drugs currently in trials in AIDS patients, there are not yet sufficient data to establish their effectiveness in the treatment of AIDS. There are a few compounds, however, for which there is some preliminary clinical evidence of possible usefulness in the treatment of AIDS or opportunistic infections. In the absence of complete data, the possibility exists that these compounds may also have a deleterious effect, such as enhancement of viral replication and shortening the time of disease progression.

The FDA has procedures which allow for the limited availability of drugs for serious, life-threatening situations where only preliminary evidence of possible clinical usefulness of the drug is available. These are called compassionate or treatment IND's. The FDA has worked with those companies or investigators that wish to make their compound available in this situation while the definitive studies to establish efficacy are ongoing.

The FDA has offered its assistance to expedite and facilitate the filings of IND's to foreign as well as domestic firms.

I wish to stress that we are most concerned with facilitating the availability of any product that appears to be useful in treating AIDS victims, and we are prepared to work with anyone willing to sponsor clinical investigations consistent with our obligation to safeguard patients used as research subjects.

Finally, an overview of PHS activity with regard to treatment. It is clear that we have made tremendous progress in a short period of time, but we are still far short of an effective therepeutic modality. Immediately after the identification of the disease, research was initiated by the PHS. Initially the major effort was by the PHS intramural research laboratories because of the ease logistically of mobilizing resources and changing research direction in the NIH intramural program, but with time, and as we learned more about the disease, the effort increased and moved more to the extramural community.

This chart shows the relationship between extramural and intramural funding for AIDS and shows how extramural spending has gone up proportionately to intramural spending as time has gone

on.

The next chart shows the amount of funding, fiscal years 1982 through 1985, for all AIDS extramural and intramural activities at the National Institutes of Health.

As new insights into the treatment of AIDS emerged, an extensive series of outreach programs and seminars have been carried out to widely disseminate information. Over the past 2 years, the

NIH has sponsored treatment worshops on both the infectious complications of AIDS and HTLV-III. The NCI held a workshop dealing exclusively with human retroviral diseases in December 1984. NIAID has sponsored nine outreach programs in metropolitan areas across the country. It also sponsored meetings at the Rocky Mountain Laboratory in November 1984, and, in conjunction with the NCI at the national clinical meetings, in May 1985. The PHS recently held a workshop on antivirals at NIH. We would like to submit for the record a copy of the report resulting from that workshop.

Mr. WAXMAN. Without objection, it will be included in the record. [See p. 47.]

Dr. MASON. Under the overall guidance of the PHS Executive Task Force on AIDS, we have established a Task Force on Vaccine Development and Therapeutic Intervention under the chairmanship of Dr. James Wyngaarden, Director of NIH, to coordinate and expedite research efforts on therapeutic modalities. This is being accomplished by giving special priority to grant applications in this area, increasing intramural research efforts, expediting reviews of IND applications by the FDA and the issuance of requests for applications [RFA], and/or proposals [RFP]. We are carrying on these activities in an effort to optimize our research.

NIAID has recently released an RFA requesting applications for comprehensive studies of AIDS, including epidemiology, basic research, pathogenesis, treatment, and prevention, and clinical trials. There exists an array of distinct but complementary research efforts throughout the United States-and especially in regions where there is a high incidence of AIDS-pursuing many promising leads for improving therapy of AIDS patients. The next step is to link these activities and their results to a closely coordinated network of hospital-based research units in which patients with AIDS can gain access to the expected new therapies on a carefully controlled experimental basis, on its beneficial effect on studies.

The time is now for such a coordinating mechanism. Dr. Wyngaarden already has taken steps to establish this network.

I am confident that effective means for clinical testing for new AIDS therapies will be in place to exploit the new basic therapeutic developments we are now seeing.

In addition to the therapeutic approaches I have outlined, the PHS is working on a vaccine to prevent AIDS. We have also developed a comprehensive plan for control and prevention of AIDS that emphasizes education and information activities, and includes a framework for the research that we have discussed today.

This concludes my statement, Mr. Chairman. My colleagues and I would be happy to answer any questions you might have. [Testimony resumes on p. 55.]

[The prepared statement of Dr. Mason and report referred to follow:]