Gay Men's Health Crisis "Treatment Issues", Vol 8, No. 10, November, 1994
Vincent Pieribone, Ph.D.

The NCDDG-HIV was established in 1986 specifically to provide financial support for scientists interested in developing innovative anti-HIV therapies. Scientific investigations into the virus's lifecycle are largely performed at academic research institutes supported by the NIH. Drug screening and clinical trials are performed by sponsoring drug companies and NIAID's AIDS Clinical Trials Group.

Very often, though, observations made about the HIV lifecycle that might have therapeutic application go unexplored by academic researchers and drug companies. This large gap, between studying the virus's lifecycle and screening candidate drugs, is where the NCDDG-HIV stepped in. By nurturing collaborations between basic scientists and drug companies, NCDDG grants attracted proven researchers with sound therapeutic concepts into embarking on risky drug discovery projects. Collaborating companies could guide the scientists until their concepts were ready for the company to test.

The progress made through NCDDG-funded grants have been substantial. Research funded by this program has resulted in the development of assays for measuring gag-gag and integrase-integrase interactions (both necessary for viral infectivity) that are now used to screen potential treatments. A screen for novel reverse transcriptase inhibitors created through an NCDDG-HIV grant identified inophyllum B as a potent inhibitor. This compound is now in pre-clinical trials at the National Cancer Institute. Many grant recipients consider NCDDG-HIV funding to have been indispensable to their projects' advancement. One such researcher is Jef D. Boeke from Johns Hopkins University, who is investigating capsid-targeted viral inactivation mechanisms (which destroy the HIV genes within the viral core). Dr. Boeke was unable to obtain any funding to work on HIV drug discovery until his group received an NCDDG-HIV award. He then obtained further support and transformed an interesting idea into a novel and exciting therapeutic possibility.

Restrictions on the NCDDG-HIV will lead to the loss of crucial and rare collaborations. Although the program is not being killed outright, it faces two severe constraints: a phased-in reduction in the number of projects supported and a loss of the special "set-aside" fund that maintained the program as a whole.

A 1991 ad hoc NIAID committee reviewing the NCDDG unanimously concluded that "investigator initiated, collaborative, consortium type research directed at drug discovery should be fostered." But the review committee recommended that NIAID should decrease number of groups funded by the NCDDG-HIV from 27 in 1991 to eight to twelve. Its reasoning was that the "present numbers of grants of high quality do not appear to support [the current] level of funding."

The lack of quality proposals may be a sad reflection on the NIH's ability to inspire clinically related research from the hundreds of HIV basic research grantees. The agency's ability in this respect will further diminish under the current NIAID proposal to eliminate the special budgetary allocation reserved for financing the NCDDG-HIV.

In defense of this move Jack Killen, M.D., director of NIAID's Division AIDS (DAIDS) said, "We are committed to maintaining a program of eight to twelve NCDDG-HIV grants. We used to set aside money to get the program running. There is no need for that now that the program is set up. We will issue a program announcement, now being prepared, saying we welcome NCDDG-type drug design applications involving collaborations with industry."

NIAID insists that researchers who no longer obtain funding from the NCDDG-HIV can apply for traditional researcher- initiated grants (R01, or program project, grants) to continue their research. But the NCDDG was established precisely because the usual researcher-initiated granting scheme generally does not fund drug discovery research. The standard R01 review process is much too conservative to properly assess exploratory research that seeks to develop assays and therapeutic agents. R01 grants also are highly competitive. Only ten to fifteen percent (or less) of the R01 grant applications judged to have merit actually receive funding.

The worst scenario would be to require the R01 grant reviewers to evaluate all NCDDG-type research, as is now under consideration. The NCDDG-HIV had specific requirements for grants that narrowed the field of applicants, thereby increasing each applicant's chance of success. The ad hoc review committee report on the NCDDG-HIV commented, "It was agreed that the proposed cooperative agreement (U01) objectives, including 1) therapeutic endpoint, 2) multiple institution collaboration, 3) added value achieved by the collaborations, and 4) high risk innovative research, clearly distinguished this funding mechanism from R01 funded research."

Nonetheless, Dr. Killen's statement appears to represent an improvement in NIAID's position on the NCDDG-HIV. In July of this year, DAIDS' therapeutics development chief Carl Dieffenbach, Ph.D., reportedly told the National Task Force on AIDS Drug Development that the NCDDG-HIV was being phased out and that researchers could apply for other grant programs. When reproached that obtaining many grants involved a lengthy process, Dr. Dieffenbach responded that the grants he was referring to took "only two years."

NIAID furthermore recently announced a new program know as SPIRAT (Strategic Program for Innovative Research on AIDS Treatment) that is also designed to fill the gap between basic research and clinical studies. Though AIDS researchers and activists applaud the SPIRAT program, it is clear from the design of this program that the majority of projects now funded by the NCDDG-HIV would not be eligible for SPIRAT money. SPIRAT is focusing on a narrower, purportedly more advanced range of products and emphasizes phase I human trials of gene transfer and immune modulation research. In a letter sent to NIH officials Drs. William Paul (director of the Office of AIDS Research), Anthony Fauci (director of NIAID) and Harold Varmus (overall NIH director), the Treatment Action Group (TAG) expressed its surprise and dissatisfaction at the unwarranted loss of the critical NCDDG-HIV program. (This writer was one the letter's co- authors.) TAG asked for renewed set-aside funds for the NCDDG-HIV or establishment of a similar program.

Ironically, NIAID is pruning the NCDDG-HIV just at a time when the blue-ribbon National Task Force on AIDS Drug Development is concluding that bridging basic and clinical research should be a major priority for NIAID and the NIH as a whole. David Ho, M.D., director of the Aaron Diamond Center for AIDS Research and a member of the Task Force, recalled a variety of extremely promising targets in the HIV lifecycle that at present are ignored. (See Treatment Issues, October 1994, for an interview with Dr. Ho).

Very few anti-HIV approaches are available to succeed the current crop of new reverse transcriptase inhibitors and protease inhibitors, which have not yet shown a long term anti-HIV effect in initial clinical trials. The present situation is very grave: NIAID should rescue the NCDDG-HIV program by restoring funding levels and actively promoting new research in this vital area. In doing so, the Institute will renew its commitment to bridge the gap between basic and clinical HIV/AIDS research and encourage the more rapid development of anti-HIV therapies beyond reverse transcriptase and protease inhibitors.

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