AIDS Research at the NIH: A Critical Review

datasets from published ACTG studies on file with the US National Technical Information Service (NTIS)
so that other researchers can work with the data.
The Pharmaceutical + Regulatory Affairs Branch (PRAB), chief Joe Meschino, PhD, has two sections,
Regulatory Affairs and IND Management. PRAB handles investigational new drug (IND) issues with the
FDA - especially on so-called "routine" protocols in which NIAID holds the IND - and negotiates with drug
companies on pharmaceutical supplies, including blinded placebos and blister packs for clinical trials.
AIDS Clinical Trials Group (ACTG). The ACTG is the largest single AIDS program administered by NIH,
taking $92M in grants and contracts in FY 1991 and $103M in FY 1992. The ACTG accounts for oneeighth of all NIH AIDS spending. It is the program with which activists are most familiar, and the one which
they have changed most. In 1985 NIAID released a Request for Proposal (RFP) for AIDS Treatment
Evaluation Units in an effort to fund a multicenter clinical trials network. 14 ATEU contracts were awarded
in June 1986. In January 1987,5 additional ATEUs were formed and NIAID funded several Clinical Studies
Groups (CSGs) through cooperative agreements. After Dan Hoth was named Director of NIAID's AIDS
Program in October 1987, the ATEUs and the CSGs merged into the cooperative-agreement (U01) funded
AIDS Clinical Trials Group (ACTG). The ACTG cost $92M in 1991 (counting both grants and contracts);
it is projected to spend $103M in FY 1992 [a total of $465 million between 1986-92].
The ACTG has conducted almost 200 clinical trials of scores of drugs enrolling 19,330 patients. ACTG
studies led to approval of AZT for people with CD4<500 (016, 019) and for children (003, 043); they also
led to halving the licensed dose of AZT from 1200 mg/day to 600 mg (002, 010, 019). The ACTG brought
ddl from phase I study (064) through to licensure on the basis of surrogate markers in 1991 and follow-up
proof of clinical benefit in 1992 (116B/117). The ACTG also conducted phase I, phase VII/ and phase IVIII
studies of ddC, some of which (012, 047, 050, 106, 114, 119) were included in the Roche NDA submission
which was approved in summer 1992. The ACTG also demonstrated antiretroviral activity of d4T in a
phase I trial (089), but decided thereafter to let industry pursue efficacy studies of additional nucleoside
analogues.
The ACTG demonstrated the following agents to have little or no antiretroviral activity at the doses used:
ribavirin (034, 035, NS403), AL-721 (022), dextran sulfate (060, 078, 105), recombinant soluble CD4 (066,
101, 121), N-butyl-DNJ (100), ampligen (038, 054, 056), and recombinant tumor necrosis factor with or
without recombinant interferon gamma (025). ACTG studies of recombinant Interieukin-2 (rlL-2; 024, 042,
067) and of autologous CD8 cells expanded ex vivo with a cocktail of recombinant cytokines (080)
suggested but did not prove that they are active and should be subjected to further study.
In the realm of opportunistic infections, ACTG studies (026, 059) contributed to licensing of fluconazole for
cryptococcal meningitis. ACTG 159 is attempting to identify the optimal induction and maintenance
regimens for this disease. The ACTG has also demonstrated the efficacy of itraconazole (084, 120) for
histoplasmosis, but these studies have not been published, nor has the FDA licensed the drug. ACTG 021
concluded in 1991 that trimethoprim-sulfamethoxaxole was more effective than aerosolized pentamidine
in preventing a second episode of PCP; a comparison of those agents with dapsone as primary prophylaxis
is ongoing (081). ACTG 015 was included in the NDA of foscamet for CMV retinitis. The SOCA study
ACTG 129 suggested that foscamet may provide a survival benefit as compared to ganciclovir in people
on CMV retinitis maintenance therapy. The ACTG has also worked on studies of novel anti-herpesvirus
agents and indications, such as foscamet for acyclovir-resistant herpes (095), oral FIAC/FIAU (122) and
oral ganciclovir (127). ACTG 981 may suggest the best antifungal prophylaxis (fluconazole or clotrimazole),
if any. ACTG 113 showed that spiramycin was ineffective as treatment for cryptosporidiosis. ACTG 135
may help to define a multi-drug standard of care for MAI, and 157 demonstrated anti-MAI activity of
clarithromycin. ACTG 154 is studying pyrimethamine with leucovorin rescue for toxoplasmosis prophylaxis,

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