A National AIDS Treatment Research Agenda

V International Conference on AIDS
Montreal, June 1989

Revised: September, 1989

AIDS Coalition to Unleash Power/New York

ACT UP is a diverse. non-partisan group of individuals united in anger and committed to direct action to end the AIDS crisis. We protest and demonstrate; we meet with government and public health officials; we research and distribute the latest medical information.

496·A Hudson St. Suite G4
New York, NY 10014


  1. 12 Principles for a New AIDS Drug Testing System

  2. New Models for Clinical Trials

  3. The Parallel Track

  4. AIDS Clinical Research Priorities

  5. AIDS Drug Development Disasters


The US is the epicenter of the worldwide AIDS pandemic. It has the resources – human, technological and financial – to rapidly develop drugs to prevent or treat most AIDS-related conditions. It has a global responsibility to do so. The US has failed to carry out its global responsibility. The managers of the AIDS research effort are motivated by profits, patents and prestige, not by a vision which demands solutions to the real-world problems engendered by AIDS.

Over the last year, dimly, like echoes from a distant battlefield, the voices of people living with AIDS or HIV and their advocates have begun to reach the ears of researchers and regulators in the Federal AIDS establishment, who have finally begun to notice that something is wrong.

The crisis engendered by the dysfunctional drug development status quo may well cause consternation and conflict among US scientists and regulators. Its grimmest consequences, however, are played out every day in hospitals and clinics and, increasingly, in streets all over the world. The toll of unnecessary sickness and early death caused by HIV-related conditions mounts relentlessly while people worsen from lack of access to existing drugs of known safety and very strong indications of efficacy.

It is time to develop a comprehensive strategy to address all clinical manifestations of HIV. The US AIDS Program does not have such a strategy. We have no time to wait for them to develop one. People living with AIDS/HIV and their advocates know what must be done. The following is a set of guidelines for a sweeping revision of US AIDS research and regulatory priorities. We call upon all people working in the struggle against AIDS to put these guidelines to work.

12 Principles for a New AIDS Drug Testing System

Studies are constantly announced and undertaken by people who have only the vaguest notions of how we live.

– Larry Kramer, “Where Are We Now?” October 1982

Trials serve a dual role: researchers and sponsors want data which may lead to marketing approval; subjects want health care. Therapy is the only reason potential subjects should enroll in a trial. We will not participate in a trial unless it provides treatment for the condition being researched. No trials now underway will succeed, nor should future trials be designed, without meeting the following prerequisites:

  1. People with AIDS, HIV, and their advocates must participate in designing and executing drug trials

    The AIDS community must be an equal partner with sponsors, researchers and the Federal AIDS Program in setting priorities for AIDS treatment research, selecting drugs to be tested, and designing and implementing protocols. We must have full voting members of every decision-making body involved in the AIDS Program, including:

    • NIAID’s AIDS Clinical Trials Group (ACTG) Executive Committee,

    • NIAID’s AIDS Clinical Drug Development Committee (ACDDC),

    • FDA advisory committees concerned with AIDS treatments,

    • Institutional Review Boards (IRBs) at all sites conducting AIDS and HIV-related clinical trials,

    • The National Committee to Review Current Procedures for Approval of New Drugs for Cancer & AIDS (the Lasagna Committee), and

    • The Parallel Track Advisory Committee.

  2. A comprehensive, coordinated, compassionate drug-development strategy must ensure that all promising agents are evaluated thoroughly and, if effective, distributed rapidly

    The AIDS Program has no master strategy. NIH continues to rely on investigator-initiated research, delaying even the best proposals in a bureaucratic labyrinth. This passive approach produces treatment advances in bits and pieces. An overall research strategy should be coordinated with the AIDS community to develop a comprehensive plan to treat the serious infections and conditions associated with AIDS.

  3. Resources must be focused on drugs which treat or prevent opportunistic infections, not just on antiretroviral drugs

    Most Federal research dollars fund expensive, highly toxic antiretroviral trials while people with symptomatic HIV are dying of opportunistic infections that receive little attention. No current approved treatment exists for most HIV-related OIs, including CMV, MAI, HIV wasting syndrome, cryptosporidiosis, and HIV encephalopathy.

    Treating or curing the major opportunistic infections must immediately become a priority equal to finding anti-HIV agents.

  4. End the exclusion of women, poor people, people in rural areas, people of color, drug users, prisoners, hemophiliacs and children from experimental treatments. Expand staff and facilities in areas with high concentrations of HIV-infected people so trials can take place there

    Trials should allow the participation of all infected groups. Most people living with HIV lack access to new treatments which could save their lives. Resulting data describes the new drug results only in selected, homogeneous groups, not in the overall HIV-infected population.

    Children with AIDS still cannot obtain AZT outside of trials, more than 2 years after it was approved for adults.

    Federally-sponsored drug trials should fund primary-care physicians in areas where enrollment is impeded when principal investigators do not enroll patients who lack primary-care physicians.

  5. End the exclusion of AZT-intolerant individuals from trials for infections or other antivirals

    50% of people with AIDS are intolerant of AZT. They are effectively quarantined from most antiretroviral trials, which either still test AZT or compare it with newer antiretrovirals. Randomized, comparative trials bar people intolerant of AZT from access to the very drugs which offer them the best hope for treatment.

    Randomized comparative trials using AZT should have a non-randomized arm for the AZT-intolerant. Trials for anti-infective drugs should allow people to enroll regardless of their AZT tolerance. Trials that compare a new to a standard treatment should include a non-randomized, open-label arm for people intolerant to the standard treatment. For example, Foscarnet trials should include people intolerant of DHPG, not exclude them like some do now.

    The Parallel Track initiative for expanded, nationwide access to certain promising AIDS drugs outside of controlled clinical trials offers the first real chance to end the exclusion of the AZT-intolerant from trials.

  6. Protocols should be flexible enough to accommodate new knowledge about HIV infection, allowing subjects to receive state-of-the-art care for opportunistic infections (OIs) as such standards evolve

    The major confounding factor in most clinical trials is variations in patient care. PCP prophylaxis became standard-of-care in private practice while AIDS Program trials still denied subjects prophylaxis. Up-to-date AIDS care should become standard if trials are to yield valid, replicable, real-world data. Protocols should allow subjects to use new state-of-the-art HIV and OI treatments.

  7. Trials must be designed for the real world: prophylaxis permitted, placebos avoided, efficacy criteria and endpoints humane

    • Prophylaxis for OIs must be permitted to all trial subjects. Scientific requirements for valid data should be balanced with human requirements for active, aggressive treatment.

    • Placebo trials in AIDS are a medically-sanctioned form of Russian roulette. Placebo-controlled trials do not yield quick, clean data. Participants take drugs off trial, obscuring results. Target enrollment is frequently expanded to minimize data contamination from those who drop out or take concurrent medication. Trials are prolonged, results delayed, and more people exposed to risk.

      No potential trial subject with even a vestigial instinct for self-preservation will join a placebo-controlled trial. If a standard treatment exists, new treatments can be compared to that. If no approved treatment exists, new treatments can be tested against each other.

    • Efficacy criteria should be reasonable. FDA has delayed release of blood-boosting drugs like EPO and GM-CSF, insisting that they show direct clinical effects when, in many cases, those drugs merely bring blood counts up to levels where it is safe to use other treatments.

    • p24-antigen positivity should not be used as a strict inclusion criterion. Some of the AIDS Program’s newer trials require a positive p24 antigen test for inclusion. Most clinicians agree that p24 is an imperfect surrogate marker of viral activity. Not all people with AIDS are p24-positive, and some p24-positive people have no symptoms whatsoever.

    • Endpoints well short of death should be established. Death or progression of infection are unacceptable endpoints for trials when any treatment at all exists outside of trials.

  8. Clinical costs associated with trials and not paid for by sponsors should be funded by third-party payers to insure that personal income is not a de facto exclusion criterion

    HCFA (the Health Care Finance Administration), the insurance companies, NIH and drug sponsors must agree on a formula to cover clinical costs associated with administration of investigational substances: hospitalization for catheter insertion, lab costs, etc., so people of all economic strata can participate in drug trials. Third-party reimbursement must include, but not be limited to, Treatment IND and compassionate-use protocols. All society benefits from drug development. Trial subjects contribute their bodies for research. They should not have to pay for access to investigational substances.

  9. The Orphan Drug Act should be reformed so that products developed at public expense are priced fairly. In return for its multi-million-dollar investment in AIDS research, the government is entitled to demand low-cost drugs for AIDS. This will make treatments accessible to people who can’t afford AIDS drugs in both the US and worldwide

    Few remember that the drug-law reforms of 1962, originated in Senate hearings over inflated new-drug prices. The outrageous price of AZT was one of the reasons ACT UP formed in 1987. Several pharmaceutical companies are exploiting the AIDS crisis and the Orphan Drug Act to jack new drug prices up to unprecedented heights.

    Most research costs for new drugs for AIDS are paid for with tax revenues. ¾ of all people in the ACTG system are still in AZT trials. AZT research is massively subsidized by the public while huge profits are privatized in the hands of Burroughs Wellcome. If AZT is approved for high-dose use in asymptomatic HIV-infected persons, the company will make billions. This makes a mockery of the intent behind the Orphan Drug Act.

    In the case of erythropoietin (EPO), orphan drug status actually impeded release of the drug, as companies fought for pieces of the lucrative market.

    Orphan Drug status is really a taxpayer subsidy for pharmaceutical research. The public is entitled to a fair return on its investment in the form of a reasonable price. Companies should substantiate their prices for orphan drugs and open their books. Drugs developed at public expense should be licensed to competing sponsors to keep prices down. Orphan Drug status should be revocable if a drug (e.g., AZT, EPO) becomes unexpectedly lucrative. If a sponsor drops a promising drug, compulsory-licensing procedures should be available, as they are in Canada.

  10. The community-based clinical trials network, NIH, FDA and other drug development agencies hire increased staff, funding and facilities to wage a successful effort against AIDS

    At a fraction of the cost of AIDS Program trials, New York’s Community Research Initiative (CRI) and San Francisco’s County Community Consortium (CCC) have already provided the data necessary for aerosol pentamidine to receive Treatment IND status and a recommendation for full approval. Three years and half a billion dollars later, the Federal AIDS Program has yet to produce a single drug for wide use. If a cure for AIDS were discovered tomorrow. the AIDS Program would not be able to test it for over a year. NIAID has not run its multicenter efficiently or set up good, quick trials. Staff and funding increases are necessary, but not sufficient, to improve its performance.

    Because there is no overall AIDS treatment development strategy, the US has no grasp of the overall logistical needs for conducting widespread clinical trials. A comprehensive response to AIDS would include more doctors, nurses and lab technicians in Health Manpower Shortage Areas, particularly researchers, clinicians and nurses of color.

    The US has the ability to expand funding in all areas of health care. What has hitherto been lacking is the political will to do so.

  11. Establish an accurate, up-to-date, accessible, international registry of clinical trials and promising experimental treatments for HIV and for AIDS-related opportunistic infections

    Drug sponsors are hoarding information on life-saving treatments during an international pandemic. This is unconscionable. All trials, both Federally-sponsored and pharmaceutical, should be listed in a nationwide database when they begin. The Public Health Service (PHS) agencies should cooperate with groups like New York’s AIDS Treatment Registry (ATR) to demand information from pharmaceutical companies and make up-to-date information available to everyone. PHS officials should support legislation making all clinical trial information available to the public.

    FDA and NIH should help to establish international standards for exchange of drug trial data, creating international standards which could speed the availability of foreign-tested drugs to Americans and vice versa.

  12. Promising new treatments for HIV and AIDS-related infections should be made accessible to anyone without regard to personal income

    FDA should become a proactive agency which protects Americans from deadly diseases, not just from unproven treatments.

The Treatment IND has failed to widen access to promising experimental treatments. FDA should reform or replace its failed program to allow distribution of promising experimental substances to all who need them before full marketing approval.

A new distribution network for promising experimental treatments is needed. It should provide both primary health care and access to safe investigational substances believed effective. Data forms should be simple (like those of San Francisco’s County Community Consortium) so participating physicians aren’t swamped with paperwork. The FDA should immediately acquire on-line computer systems to evaluate trial data.

Companies have no financial incentive to apply for Treatment IND. Few have. The Health Care Financing Administration (HCFA), which funds Medicare, refuses to acknowledge the therapeutic intent of the program embodied in its name. Following its cost-ineffective lead, other third-party payers refuse to pay for these promising drugs. People with money can pay for access to life-saving treatments, while people without money suffer more and die faster.

Most people with AIDS lack access to information about Treatment IND and compassionate use drugs. Most doctors are ignorant of them. Most inner-city and rural hospitals lack staff and funds for clinical procedures associated with such drugs, even when the drug itself is provided free. Physicians lack time or staff to complete the rigorous paperwork.

At the end of the first decade of the AIDS pandemic, we have a historic opportunity. For the first time, there is an array of promising substances ready for human testing. They should be widely distributed in treatment protocols to treat AIDS-related infections and directly combat HIV. If clinical trials continue to be badly designed, the increasing AIDS caseload will overwhelm our society. If the Federal AIDS Program and the pharmaceutical industry work with the AIDS community to create a humane research system patients and science will both benefit.

New Models For Clinical Trials

We need to consider alternative study designs that offer the patient maximum hope for cure and the opportunity for some control over his or her destiny. What I am suggesting is the need for a reexamination of all the assumptions on which the scientific requirements of the present system are based.

– Jere T. Goyan, Ph.D., Ex–FDA Commissioner, UCSF Pharmacology School Dean, “Drug Regulation: Quo Vadis?” 1988

There is an urgent need for new AIDS clinical trial designs. Only about 7,000 Americans, less than 0.5% of the HIV-infected US population, have enrolled in an AIDS clinical trial. Accrual is impeded by poor trial design, inaccessibility, denial of opportunistic-infection prophylaxis, reluctance to enroll in placebo-controlled studies and ineffective outreach to the affected communities.

A consensus is developing among the medical establishment and the AIDS community. We need better trials carried out in new, community-based institutions. Computer monitoring of serologic and clinical results can be used to evaluate optimal dosages and combinations of drugs for HIV-related conditions. New models for clinical trials will synthesize scientific and therapeutic aims.

The Parallel Track

[Note: the following is the consensus statement of 15 AIDS research, service and advocacy organizations presented to the FDA Anti-Infective Drugs Advisory Committee on August 17, 1989, and ratified by that committee in its recommendations to FDA and to Assistant Secretary of Health James Mason.]

The concept of Parallel Track permits the treatment use of experimental drugs while controlled efficacy trials are ongoing, thus offering earlier access to promising new treatments to people with AIDS and HIV-related conditions. This concept has been widely hailed. The AIDS community is eager to work with FDA, NIH, pharmaceutical sponsors and researchers to rapidly define and implement the Parallel Track.

Parallel Track offers the best hope to address some of the most urgent problems posed by the AIDS epidemic: the rapidly expanding caseload, the proliferation of new promising treatments, the inability of traditional research institutions to test each promising therapy, the inability of most HIV-infected Americans to enroll in controlled clinical trials, and the use by many patients, out of necessity or choice, of other medications.

The importance of Parallel Track lies in its potential to offer the widest possible access to new drugs for people who lack other-than-experimental treatment options, and to make it possible, at the same time, to proceed efficiently with drug licensing.

Existing mechanisms to widen availability of new treatments outside of controlled trials, such as Treatment IND and Compassionate Use IND, have met only a fraction of existing needs. Parallel Track may resolve access needs, provided, we believe, the principles outlined below guide the implementation of the Parallel Track concept.


Parallel Track should encompass post–Phase I open label treatment protocols for people unable to participate in controlled clinical trials for AIDS and HIV-related treatments. Drugs should be eligible for Parallel Track as soon as a tolerably safe dose range has been defined and preliminary evidence of efficacy has been obtained.

Drugs qualifying for Parallel Track should be accessible nationwide to qualified physicians in private practice, community hospitals, community-based health institutions, and public health clinics in addition to academic clinical research institutions.

Adverse-reaction data should be gathered on all Parallel Track subjects. Whenever possible, efficacy data should be gathered as well, through organizations such as community-based research groups. The resulting data on interactions between the Parallel Track drug and concomitant medications forbidden in controlled trials would provide valuable real-world information at the earliest possible time.


Patients’ eligibility for treatment under Parallel Track should be determined by qualified physicians on a case by-case basis. However, the same access criteria should apply under different circumstances. The following groups of HIV-infected individuals should have access to treatment under Parallel Track:

Because of the generally large number of people with AIDS and HIV disease, and because most of them will be unable to participate in controlled clinical trials, it is anticipated that the existence of Parallel Track will not compete with, but rather complement, more formal studies.


Decisions regarding the definition and implementation of Parallel Track should be made by a Parallel Track Advisory Committee, an independent body including representatives from the Food & Drug Administration (FDA) and National Institutes of Health (NIH), but empowered with full decision-making autonomy. This committee should also have representation from top research scientists as well as the Health Care Financing Administration (HCFA), to assist it in advising on issues of third-party reimbursement for ancillary costs associated with Parallel Track drugs, including costs of administration and adverse-reaction monitoring.

The Advisory Committee would also contain representatives from the Pharmaceutical Manufacturers Association (PMA) and an ad hoc position for the sponsor of the drug in question, and top research scientists.

Most importantly, the Parallel Track Advisory Panel must include full, voting representation by AIDS primary-care physicians, representatives of community-based research groups, and people with AIDS, HIV and their advocates. It is the lack of such decision-making representation that has impeded all previous efforts at widening access to new AIDS therapies. If this participation is once again limited, the program may well generate the same disappointing results as Treatment IND and Compassionate Use.

As one of its first tasks, the Parallel Track Advisory Committee should consider mechanisms for assuring that any person with HIV infection who has a demonstrable medical need for a Parallel Track treatment could obtain access regardless of economic circumstances.

AIDS Clinical Research Priorities

6 Drugs We Need Now
8 Treatments We Want Tested Faster
Passive Immunotherapy
Peptide T
Guidelines for Research
Prophylaxis for OIs
Treatment for OIs
Blood Conditions
Wasting & GI Conditions
Neurological Conditions
Addiction Treatments
Complimentary Treatments

6 Drugs We Need Now

Enough is known about the following 6 treatments to release them in broadly-inclusive treatment protocols now. Such a program (which could be under the auspices of the Parallel Track) should include:

  1. ddI (dideoxyinosine). In the test tube, ddI is slightly less active than AZT, but many times less toxic. Phase I trials showed toxic pancreatitis and peripheral neuropathy at high doses, but these are reversible, and may not occur at the lower doses projected for the Phase II trials. DDI crosses the blood-brain barrier, essential for suppressing HIV in the brain. It languished for a year in endless Phase I dose-escalation studies. When Phase I trials show safety, Phase II trials should be allowed to begin while small Phase I studies for the maximum tolerated dose continue. In such cases, the toxic dose is probably much more than the necessary effective dose anyway.

    DDI could be a good treatment for:

    • People who cannot tolerate AZT at all,

    • People who become anemic on AZT and need transfusions,

    • People with CMV retinitis who need to take DHPG, which usually cannot be taken with AZT because both suppress bone marrow,

    • People who have low white blood cell counts from AZT, DHPG or pyrimethamine, a common treatment for toxoplasmosis.

  2. EPO (erythropoietin). EPO, a genetically-engineered version of a naturally occurring human enzyme, causes proliferation of red blood cells in people with AZT or HIV-related anemia, kidney disease or cancer. It can raise people’s hemoglobin counts and reduces their need for transfusions. Its approval was delayed for several months by lawsuits among the sponsors. Ortho Pharmaceuticals was recently granted Treatment IND status for EPO in AIDS-related anemias. This program is currently limited to 30 physicians nationwide. EPO’s Orphan Drug status was exploited by sponsors who defined its indications narrowly, knowing the drug will have an enormous market. (One industry insider said “This is bigger than Valium.”) It is time to amend the Orphan Drug Act to end such abuses.

    EPO could be useful for:

    • People who have anemia from taking AZT and need frequent blood transfusions,

    • People who have anemia from HIV.

  3. Fluconazole. Fluconazole is an antifungal drug effective against cryptococcal meningitis and, possibly, candida (thrush). It’s taken orally and is less toxic than the IV-administered approved alternative, Amphotericin-B. Fluconazole should immediately be granted Treatment IND status.

    Fluconazole could be useful for:

    • People with acute cryptococcal infections,

    • People on cryptococcus maintenance therapy,

    • People whose candidiasis (thrush) does not respond to ketoconazole (lizoral).

  4. Foscarnet. Foscarnet is a broad-spectrum antiviral with in vitro activity against herpes, Epstein-Barr, shingles, CMV and, possibly, HIV itself. In the US it is being tested mainly against CMV. Like DHPG, it is administered IV, but unlike DHPG, it is not bone-marrow-suppressive. So it can be taken along with AZT. Its sponsor, Astra, restricted compassionate use to people who already have life-threatening septic infections from DHPG-induced low white counts.

    Foscarnet could be useful for:

    • People who cannot tolerate DHPG because of low white blood cell counts,

    • People who want to treat their CMV while staying on AZT,

    • People who fail on DHPG,

    • People whose CMV becomes resistant to DHPG,

    • People whose herpes becomes resistant to acyclovir.

  5. GM-CSF (granulocyte-macrophage-colony-stimulating factors). GM-CSF, a genetically engineered version of a naturally occurring human enzyme, causes proliferation of 2 vital types of white blood cells. low white cell counts can cause life-threatening bacterial infections. GM-CSF can reverse the bone-marrow toxicity of drugs like AZT, DHPG or cancer chemotherapy, enabling subjects to take treatments which can extend their lives. GM-CSF should not be taken in the absence of antiretroviral therapy. Some reports indicate taken alone, GM-CSF may accelerate HIV replication.

    GM-CSF could be useful for:

    • People whose white blood counts (WBC) is too low for them to take AZT or DHPG,

    • People who develop low WC on AZT or DHPG,

    • People whose WBC is too low to take cancer chemotherapy.

  6. ddC (dideoxycytidine). ddC, a potent nucleoside analogue once considered too toxic for widespread clinical use, has proved acceptable when used in far lower doses, intermittently, or in alternation with AZT. It should be tested widely at these safer low doses. The intermittent and AZT-alternating studies should provide the impetus for creative new strategies of combination antiretroviral therapy.

    ddC could be useful for:

    • People who are intolerant of or resistant to AZT.

    • People who cannot stay on AZT because of concomitant myelosuppressive medications like pyrimethamine, DHPG or Bactrim.

    • People who are failing on AZT.

8 Treatments We Want Tested Faster

The following treatments should be tested faster.

  1. Ansamycin. This antimycobacterial has been available from the CDC for compassionate-use treatment of MAI. Recently, however, the FDA told ansamycin’s sponsor, Adria Labs, that if it wanted to get the drug approved, it would have to end compassionate use and conduct controlled clinical trials. Why can’t both be done together? As a result, ansamycin, one of the least toxic and more effective treatments in the unimpressive armamentarium of anti-MAI drugs, is virtually unavailable. It has been reported to have anti-HIV activity as well.

  2. CD4-exotoxin, CD4-immunoadhesin. First-generation CD4’s Achilles heel is its short half-life in the bloodstream – about one half-hour. To be effective the drug would have to be injected many times a day. Yet by attaching an HIV antibody (immunoadhesin) or a toxic plant protein (exotoxin) to the CD4 molecule, the serum half-life can be extended to 2–3 weeks, long enough to make this a convenient antiviral treatment. Phase I studies of these 2nd-generation CD4s should begin immediately, with studies of first generation CD4 continuing to determine longer-range side effects. Efficacy trials should focus on the more practical, convenient 2nd-generation products. The CD4 exotoxin might both prevent HIV from attaching to susceptible cells and kill infected cells.

  3. ddC (dideoxycytidine). In vitro, ddC is more potent than AZT. Early clinical studies showed unacceptable toxicity, especially with the incidence of irreversible peripheral neuropathy, but later studies, using a lower dose, were more promising. Used in alternation, or in low-dose combination, with AZT, ddC may help reduce the risk of viral resistance to antiretroviral treatments. Given the pressing need for new antiretroviral regimens, ddC should be in wider trials at the less toxic lower dose now.

  4. Diclazuril. Gastroenterologists are up in arms about the Federal AIDS Program’s refusal to put diclazuril into clinical trials for treatment of cryptosporidiosis, a devastating protozoan infection that causes diarrhea. Existing treatments are ineffective. The AIDS Program failed to act on 2 successive protocols to test new agents, spiramycin and diclazuril, against cryptosporidiosis. It was just another omission by the AIDS Clinical Drug Development Committee (ACDDC), which meets only 3 times annually and won’t consider diclazuril because the principal investigators didn’t send in the requisite number of copies. Concerned with maintaining its own procedural regularity, the ACDDC is blocking promising anti-infective treatments from the clinical pipeline. As with aerosol pentamidine, a private pharmaceutical will have to step in where NIAID feared to tread.

  5. Hypericin. Hypericin, an herbal extract, inhibits assembly and budding of viral particles from infected cells. Virus-infected mice survived 23 days untreated, 70 days on AZT, and over 240 days on Hypericin. AZT and Hypericin were found to be synergistic. Hypericin blocks syncytia formation in the test tube. No toxicity has been observed. The half-life in mice and monkeys is 2–3 weeks. Hypericin may be active against herpes as well. Cheap and nontoxic, it is a good candidate for combination antiviral trials.

  6. Passive immunotherapy. Plasma rich in HIV antibodies is extracted from healthy seropositive donors and injected into people with AIDS. Two separate uncontrolled studies in England showed striking clinical benefits, remission of symptoms, and improvements in T4 cell counts. Studies in the US have been delayed by lack of funding. This treatment deserves top research priority.

  7. Peptide-T. This sequence of amino acids is designed to block HIV’s attachment to the CD4 receptors of HIV-susceptible cells. It penetrates the blood-brain barrier, unlike recombinant CD4, which otherwise is designed to achieve a similar result. Preliminary results from Phase I studies indicate remission of symptoms such as rashes and stabilization or improvement of blood markers. Substantially nontoxic, Peptide-T should be in wider efficacy trials.

Antiretroviral Treatments

You’re going to freeze yourself into one moderately successful drug to treat AIDS.

– Samuel Broder, MD, NCI Director, to the FDA at the Lasagna committee, 1.4.89

Too much research is focused on nucleoside analogues and their reverse transcriptase (RT) inhibitory activity. There are many ways to inhibit HIV, including:

Nucleoside analogues less toxic than AZT should become standard (e.g. DDI). If viral resistance is feared, than an alternating regimen of 2 less-toxic RT inhibitors should be developed. The DDC/AZT alternating regimen is probably too toxic. Once satisfactory less-toxic RT inhibitors are identified, research should focus on combination antiretroviral regimens utilizing the mechanisms described above. Candidates for more effective reverse transcriptase inhibitors include AzdU (azidouridine), AZT-DP, D4T (found less toxic than AZT in lab and animal studies), FLT (found several times more effective than AZT in Swedish trials) and Foscarnet.

Prophylaxis for the Major Opportunistic Infections

The importance, high frequency and relative ease of study of the infectious complications of AIDS should make development of prophylactic measures a high priority.

– Jonathan Gold, MD, Memorial Sloan-Kettering, NYC, ATIN 3:4, April 1989

Community-based trial centers should focus on prophylaxis and treatment of opportunistic infections

The Federal AIDS Program has shown little interest in trials for prophylaxis or treatment of opportunistic infections. In New York City on May 30, NIAID Director Dr. Anthony Fauci attributed this to lack of sufficient interest on the part of investigators. This is spurious. Time and again, NIAID’s own bureaucracy has proved its lack of interest in anti-infectives. Aerosol pentamidine for PCP prophylaxis and spiramycin or diclazuril for cryptosporidiosis are examples.

Yet the best hope of survival for HIV-infected people is to avoid AIDS-related opportunistic infections and cancers. Community-based trials have already succeeded in gathering efficacy data on the only important AIDS-related prophylaxis to attain FDA approval (aerosolized pentamidine).

Prophylaxis for opportunistic infections would be easy to test in large, non-randomized trials, because progression to infection is easy to measure. The US government should fund community-based organizations to conduct a series of nationwide prophylactic trials. This funding should supplement the existing $6 million grant for community-based AIDS research organizations.

Treatments for Opportunistic Infections

The word “untreatable” must be banned from the lexicon of AIDS

Well-designed, quickly executed trials of prophylaxes for opportunistic infections could make the most common OIs rare within 2 years. Successful results should be rapidly disseminated nationwide. Intensive, focused research on refractory disease in cases when prophylaxis failed could produce better, less toxic, more effective treatments for those OIs.

Treatment protocols should:

AIDS Drug Development Disasters

The time is ripe to proclaim and implement a new mission for the FDA – to speed the public’s access to important new drugs. No change in the law is needed to do this – simply acceptance of the fact that past approaches have not served the public well enough.

– Louis Lasagna, MD, “Will All New Drugs Become Orphans?”

The following is a brief list of AIDS treatments whose development illustrates problems in the clinical trial status quo. DDI, EPO, Fluconazole, Foscarnet, GM-CSF, Passive Immunotherapy and Peptide T also exemplify problems with drug development, but they have been covered in Part III. Inclusion in this list is not an endorsement of the treatment.


Last summer, FDA Commissioner Frank Young attempted to justify the lack of promising new treatments for AIDS, saying “we can’t approve something that isn’t there.” He predicted that no more than 2 new drugs would be approved for AIDS-related conditions by 1991.

Thanks to unrelenting pressure by AIDS advocates, Young’s prediction proved false. In the last year, alpha interferon was approved for treatment of Kaposi’s sarcoma, aerosolized pentamidine and DHPG (gancyclovir) were designated as Treatment IND drugs and recommended for full FDA approval. EPO is on the verge of approval as well.

Humane, well-designed, quickly-executed clinical trials conducted by San Francisco’s County Community Consortium (CCC) and New York’s Community Research Initiative (CRI) produced data for approval of aerosol pentamidine. This was the most important single therapeutic advance for AIDS since 1981. In the meantime, the Federal AIDS Program has continued conducting its endless, unproductive protocols.

AIDS advocates have identified the systemic problems afflicting the scientific and regulatory body politic. The point is to solve them. As citizens of this country, we have the right to demand that our government deploy its resources to save the most lives right now. Those with the power to redirect our nation’s AIDS research effort must listen to and work with us. We will not rest until they do so.