AIDS Treatment News #145, February 21, 1992
John S. James

ddC (2',3'-dideoxycytidine), an experimental antiretroviral, is a nucleoside analog (in the same class of drug as AZT). ddC, which has been available from chemical supply houses for years (it is used in DNA experiments in laboratories) was one of the first drugs tried as an anti-HIV treatment. But nobody knew that the appropriate dose was very small -- a hundred times or more less than the dose of AZT or ddI. Therefore the first trials used doses which were far too large, which caused serious, crippling neuropathy. As a result, researchers largely lost interest in the drug for about two years. When it was learned that lower doses might be tolerable and effective, interest revived; there have now been over 20 human trials of ddC that are either finished or ongoing.

The most scientifically definitive trial of ddC as a single- drug treatment for patients without prior AZT therapy recently ended in failure. The trial, known as ACTG 114, tested ddC alone vs. AZT alone in patients with AIDS or advanced ARC. This national study, with more than 600 volunteers, was stopped a year earlier than planned, by the study's Data Safety Monitoring Board, or DSMB (which periodically meets and secretly "unblinds" the trial, to see if the results are so extreme that it would be unethical to continue). The DSMB found that there were 59 deaths in the 320 patients assigned to ddC, compared to 33 deaths in the 315 assigned to AZT -- meaning that AZT clearly worked better when used as a single drug, at least at the doses being tested. (ddC might still be used for patients who cannot tolerate or no longer respond to AZT and have no other choice; trials to test this use are continuing.)

Even before this result came out, almost all of the interest in buyers' club ddC concerned its use in combination with AZT, not its use as a single drug.

ddC and AZT In Combination

A small clinical trial of HIV treatment with a combination of AZT and ddC was finished in November 1990, but not formally published for over a year (TC Meng and others, Combination Therapy with Zidovudine and Dideoxycytidine in Patients with Advanced Human Immunodeficiency Virus Infection: A Phase I/II Study, Annals of Internal Medicine, January 1, 1992, pages 13-20; also see accompanying editorial by Anthony S. Fauci, M. D., pages 85-86). Project Inform and AIDS TREATMENT NEWS published the major results of this study in November 1990 (see "ddC/AZT Combination: Promising Early Results," AIDS TREATMENT NEWS #115, November 23, 1990). In June 1991 the results were presented at satellite seminars at the VII International Conference on AIDS in Florence.

In any event, long before the scientific paper was published, the results of this study had established a de facto standard of care among many of the best-informed patients and physicians -- a standard which includes a drug not officially approved for any medical use. While exact figures are not available, low estimates are that several thousand patients -- most at the suggestion of their physicians -- are obtaining ddC at buyers' clubs to use in combination with AZT, which they obtain by prescription. But this major growth of combination anti-HIV therapy also took place largely outside of public view, as AIDS activists (including this newsletter) were concerned that too much attention could pressure the FDA to crack down, cutting off a lifeline on which thousands depended. Now the attention has come anyway -- even before the recent quality-control issue.

Behind the delay in releasing the scientific results was an intense but quiet controversy in the AIDS research community. Our best understanding of this controversy (and we cannot claim objectivity) is that the study in question, officially called ACTG 106, with principal investigators Margaret Fischl, M. D., and Douglas Richman, M. D., was designed as a small trial (with 56 patients total) to test the safety of using various doses of ddC and AZT in combination.

To everyone's surprise, not only did the combination seem safe, it also appeared to work much better than any other anti- HIV treatment known. All volunteers had AIDS or advanced ARC, with average T-cells counts under 100 at the start of treatment, but these averages went up with peak increases of at least 70 to 120 above the starting count, depending on dosage group. These T-cell rises lasted about twice as long as would have been expected with either drug alone, and over two thirds of the patients on the four appropriate combination doses had T-helper rises of at least 50 on two consecutive monthly measurements. Very few opportunistic infections occurred after the first five weeks of the study; several occurred in the first five weeks, presumably before the treatment had time to be fully effective.

Before this study, the "conventional wisdom" had been that persons with T-cell counts below 100 would not recover even if the AIDS virus could be entirely stopped, because the immune system had been too badly damaged. This small trial showed how much could be done with improved antiviral treatments alone, even without any immune-based treatment to help repair damage which had already occurred.

But this study was not designed or intended to test the efficacy of the combination treatment -- only to test its safety. The number of patients was small. The study was unblinded, and patients were not fully randomized in their assignment to treatment groups. New patients were added to the treatment groups to replace those who left, for various reasons, in the first eight weeks. The treatment groups were not always well balanced, with one dosage group having a median T-helper count as high as 103 at baseline, another a median as low as 35. (But the group which did best also started with a low median T-helper count, of 47.) And no patients received standard treatment for comparison; one group received AZT alone, but only 150 mg per day -- a dose which this study showed is too low.

These issues would not make much difference for a preliminary safety trial, but they would have been avoided in a study designed to collect definitive efficacy information. ACTG 106 was intended as a preliminary study; if results were good, it would be followed by a much larger efficacy trial. (That larger study, called ACTG 155, is now under way. It includes over 1,000 volunteers randomly assigned to one of three groups: AZT alone, ddC alone, or the combination).

What happened with ACTG 106 is that scientists and people with HIV drew different practical conclusions from it. Scientists who run clinical trials are interested in maintaining scientific standards, in doing studies correctly so that they get solid, trustworthy results. People with life-threatening illnesses, on the other hand, are interested in using whatever knowledge is available to make the best treatment decisions they can.

What has been most persuasive to us about ACTG 106 is that it is hard to interpret the outcome other than as showing that the combination treatment of ddC with AZT works much better than any conventional treatment. Because of the small number of patients, it could be argued that the benefits seen might conceivably have been due to chance. But both the size and the consistency of the results makes this possibility unlikely.

Why doesn't the FDA just approve ddC? (Over a year ago, a formal petition to the FDA by organizations representing almost all HIV physicians in San Francisco urged that the available data for ddC (and ddI, since approved) both be evaluated for possible approval; see "ddC/ddI Approval Update," AIDS TREATMENT NEWS, January 4, 1991.) The reason for reluctance is that the FDA would have to base approval largely on ACTG 106 -- but the Agency wants much more data than that before approving a drug. The FDA usually demands more than one study, larger studies, and studies designed in advance to test drug efficacy.

Expanded Access to ddC

It would be possible to have a regulatory system designed to approve drugs as soon as there was a rational case for physicians and patients to use them. Unfortunately, that is not the system we have. Often there is a compelling medical case for a drug long before the data available meets FDA standards for approval. To relieve the resulting harshness, a long series of early-access ideas (with names like "compassionate use," "treatment IND," "parallel track," and currently "expanded access") have been tried. All these programs have been seriously limited by the reluctance of pharmaceutical companies to pay for them. Ideas for more basic reforms have been tied up in partisan politics, with Democrats and Republicans each apparently willing and able to block plans acceptable to the other.

But expanded access is the option (other than the buyers' clubs) which is available now to provide ddC for combination therapy pending marketing approval by the FDA, for patients who cannot enter a clinical trial. Negotiations are underway at this time to liberalize the Hoffmann-La Roche program which is already supplying ddC to over 8,000 patients, to allow those receiving ddC in this program to combine it with AZT.

Even if combination treatment is allowed, there is still the issue of who will qualify. The data on combination use is for patients with T-helper counts under 200. But many patients with higher T-helper counts have been using the combination (with buyers' club ddC), since it is likely, although not yet proven, that the combination will be a more effective and lasting antiviral than AZT alone at any stage of infection.

Some patients with T-helper counts between 200 and 500 will be able to obtain treatment by volunteering for ACTG 175, a major new study which will compare four different treatment regimens: AZT alone, ddI alone, combination treatment with ddI plus AZT, and combination treatment with ddC plus AZT. ACTG 175 is now or soon will be recruiting in the following cities: Boston; Buffalo; Chicago; Los Angeles; Miami; New York City; Rochester; San Diego; San Francisco; Seattle; St. Louis; Stanford; Syracuse; and Torrance, CA; there might also be a site in Hawaii. For more information about this trial, call the AIDS Clinical Trials Information Service, 800/TRIALS-A.

Note: As we went to press, Hoffmann-La Roche announced that two new expanded-access programs would provide ddC for combination use:

"In order to make HIVID [ddC] available in the most efficient way possible, a simplified open-label program will be implemented within the next two weeks. Rapid enrollment will be enhanced through the use of streamlined entry criteria and limited data collection. Symptomatic HIV infected individuals with CD4 counts [T-helper cell counts] of 300 or less or asymptomatic individuals with CD4 cell counts of 200 or less who cannot participate in controlled clinical trials will be eligible to receive HIVID for combination use.... Physicians should call the ddC Coordinating Center at 800/ddC-21-HIV (800/332-2144) between 9 a.m. and 8 p.m. (EST) for enrollment information. Like all Roche investigational drug programs, HIVID will be provided free of charge.

"In the second program, to be designed with input from the AIDS community and the government, Roche will provide HIVID for combination therapy in healthier HIV infected individuals -- those with CD4 cell counts up to 500. This will be the first time that a so-called Large Simple Trial will be implemented in the study of an experimental AIDS drug. Roche will work with several community research consortia to initiate a trial that could potentially involve thousands of patients."

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