AIDS TREATMENT NEWS No. 113 - October 19, 1991
Denny Smith

They are azithromycin and clarithromycin, and the tantalizing potential to treat three opportunistic infections would logically give them the highest priority in AIDS research. Until now that has not been the case, and the plodding momentum of human trials of the drugs threatened to squander their value for thousands of people. Following is the clearest picture we could assemble of their current status, based on conversations with the commercial developers of the drugs, with members of the community, and with the Treatment and Data Committee of ACT UP/New York, which has posed a number of well-formulated questions to the manufacturers regarding the pace and efficiency of their investigations.

These two agents appear to be the strongest candidates for treating AIDS-related infections yet to emerge from a growing class of compounds called macrolide antibiotics. Other macrolides under study in AIDS research are roxithromycin and spiramycin. An article in AIDS TREATMENT NEWS #75, March 10, 1989, reported with optimism the potential of azithromycin and roxithromycin to treat toxoplasmosis and cryptosporidiosis. But the following June 16, 1989, issue #81 reported the failure of roxithromycin to treat advanced toxoplasmosis in humans. Spiramycin has been tested as a treatment for cryptosporidiosis, with mixed results; an oral formulation was not useful, but intravenously the drug has helped some people. Spiramycin has also been tried to prevent transmission of Toxoplasma from mothers to fetuses.(1)

None of these drugs was listed by study title in the abstracts published for the Sixth International Conference on AIDS last June, although we heard them discussed in some contexts with other treatments or infections. They will be discussed in various studies to be presented this month at the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 21-24 in Atlanta. Some of the abstracts from these studies and a few other previously published reports are referenced at the end of this article.

We contacted the manufacturers of azithromycin and clarithromycin to ask about their plans for clinical trials and any other avenues of access until their products are proven and licensed.

Both drugs are well into phase III trials in the U.S. ; both manufacturers have already applied for the NDA (New Drug Application, meaning permission to market the drug for prescription use). But the companies are pursuing Food and Drug Administration (FDA) approval for label indications not specifically related to treating AIDS. A newly approved drug, however, would be available to physicians treating AIDS infections, because an M.D. can administer a licensed treatment at his or her discretion for any diagnosis, whether named or not in the product labeling. In recent years, however, some health insurance carriers have been refusing to pay for many "off-label" uses of drugs, no matter how convincing the situation. So in spite of a physician's judgment, the exact labeling may ultimately determine who will or will not get the drug.

Both drugs also have Investigational New Drug (IND) status, for use in trials against MAI and toxoplasmosis.

Azithromycin has been studied in European trials, and is in Phase III trials in the U.S. to treat chlamydia, gonorrhea, and certain other infections not strictly associated with AIDS. It is marketed in Yugoslavia and Czechoslovakia under the brand name Sumamed, manufactured by Pliva. The pharmaceutical firm of Pfizer, Inc., holds the rights to develop azithromycin elsewhere, using the trade name Zithromax. In the U.S., the FDA is due to consider the NDA for azithromycin early next year.

An advantage of macrolides is their fat solubility, which increases concentrations of the drugs in body tissues. Azithromycin in particular surpasses the other macrolides in its "targeted delivery." Of great therapeutic value in some infections, this describes the capacity to penetrate the walls of some immune cells and remain inside for several hours; as the cells naturally migrate to sites of infections, so does their passenger, spilling out in the attack and enhancing the cell's fight against the infection.(2,3) Azithromycin is considered the prototype for developing a macrolide subclass called azalides.

Our recent report on MAI therapies in issue #109, August 17, 1990, referred to a San Francisco pilot study of azithromycin for treating MAI infections. Lowell Young, M.D., is the principal investigator of the study, conducted at Pacific Presbyterian Hospital in San Francisco; he has authored some of the past reports of in vitro macrolide studies.(4) He told us that the drug has been well tolerated in patients so far. This small, open-label study is still open to recruits because the entry criteria are strict. Interested persons can call 415/923-3262.

Pfizer researcher Scott J. Hopkins, M.D., explained to us the current status of other azithromycin studies for AIDS opportunistic infections. Pilot efforts to try azithromycin for cryptosporidiosis are being developed in the U.S. and the U.K., and for toxoplasmosis in France. The most welcome event now is the release of azithromycin through a compassionate use protocol for treating toxoplasmic brain infections in people who have failed the standard therapies, or are known to have a history of intolerance to those drugs. The protocol involves 600 mg of azithromycin daily for one month, then decreased to 600 mg weekly.

The physician requesting azithromycin must obtain at least verbal approval from an Institutional Review Board (IRB) for initial doses of the drug, and written approval for continuing access. Case report forms must be returned to Pfizer, so useful information can be compiled through this experience. Effective October 21, physicians can call Michael DeBruin, M.D., at 203/441-5701, or FAX 203/441-5702, to seek enrollment in this protocol for their patients.

Clarithromycin is a product of Abbott Laboratories, and has been approved for use in Ireland and Italy, under the trade names Klacid and Claricid. Abbott has submitted an NDA to the FDA for clarithromycin as a treatment for some skin and respiratory infections. Based on results of past studies, Abbott has plans to test clarithromycin in the treatment of toxoplasmosis and MAI, as well as for prophylaxis to suppress latent infections of the same.(5, 6,7) These plans are apparently less developed than are Pfizer's for azithromycin, described above.

A recent trial with 14 patients found a 99.98 percent reduction in MAI blood levels after six weeks' treatment with clarithromycin, compared to an increase in levels in patients receiving a placebo(5); a second phase of the trial found a 99.65 percent decrease with the drug. At the dosage used, toxicities required discontinuation of the drug by three patients. We have heard anecdotal reports of several people who found some improvement in MAI symptoms after trying a combination of clarithromycin and clofazimine, one of the standard MAI drugs.

Azithromycin Anecdotal Experience

In response to articles in recent issues of AIDS TREATMENT NEWS which raised the question of azithromycin's untapped potential, two readers called us to share first-hand experience with this drug.

The first report was offered by someone who began experiencing neurologic symptoms several months ago, and was diagnosed with toxoplasmic encephalitis after a computerized tomography (CT) scan revealed a brain lesion. These scans are not reliable for distinguishing lesions caused by Toxoplasma from those of cerebral lymphoma, and in fact this person had been diagnosed with lymphoma once before. His response to lymphoma treatment was complete, and the new lesion was not judged to be lymphoma by his physician or the consulting neurologist. So they initiated the standard treatment for toxoplasmosis -- pyrimethamine with leucovorin and a sulfonamide. When our friend developed a serious rash, the sulfa component was replaced by clindamycin, a frequent "next" choice. Unfortunately, this was followed by severe diarrhea, one of the side effects associated with clindamycin, and the treatment was discontinued.

By the time our friend could no longer tolerate either combination therapy, he had received about one month of treatment. Pyrimethamine alone is not considered adequate against active toxoplasmosis, and another CT scan showed the lesion persisting, although reduced in size by the treatments.

Our friend's doctor then offered to treat the infection with azithromycin. Upon signing an informed consent for using an investigational drug, our friend was given a loading dose of oral capsules totalling one gram of azithromycin, and then a maintenance dosage of 500 mg daily. After one week of treatment, a new CT scan showed no evidence of the lesion; another scan was performed at a different institution and verified the response.

We considered the question of whether the entire effort was applied to an incorrect diagnosis. But if the lesion had been lymphoma, it would not have been affected by any of the drugs tried, and symptoms would have lingered or worsened.

There is also the dilemma of understanding anecdotal successes -- how to know which drugs in a multiple-drug regimen obtained the response. In this case, was azithromycin effective enough to replace the established treatment, or did it only play a complementary role after those drugs brought the infection under control? It is very improbable that the lesion would regress independently after the drug combinations were stopped, given the usual course of AIDS-related toxoplasmosis. Both our friend and his physician are convinced that azithromycin controlled the infection. They saw no obvious toxicities, and in line with the established treatment regimen, a suppressive maintenance dose will be continued indefinitely.

The other report came from Larry Bruni, M.D., who treats HIV in his Washington, D.C., practice, and who has advocated for investigations of both drugs for some time. He decided to offer azithromycin to two of his patients whose bloodwork revealed past exposure to Toxoplasma, and in whom high titers pointed to an increased risk for a reactivated infection. The titers were decreased in both patients on the drug, and Dr. Bruni feels it has been effective so far in preventing active toxoplasmosis.

He also tried azithromycin with three patients diagnosed with cryptosporidiosis. One of the patients said that he doubted the drug was helping, and he was lost to follow-up early in the experiment. The other two reported good responses to the drug, and they continue to use it.

Comment Regarding Access

Unfortunately, the differences in healthcare systems and drug licensing among various countries have led to uneven access to many important drugs. In our reports of investigational treatments, we try not to take for granted the approval status of experimental drugs in countries outside the U.S., or the economic limits imposed on countless people who need AIDS treatments urgently. Where drugs are not licensed, or affordable, clinical trials may provide access to a treatment for some people. If participation in a trial is not feasible, physicians can sometimes secure an experimental drug by petitioning the manufacturer on behalf of patients in need, especially those who have failed standard treatments, or who have no other options.

We have not heard of any access to azithromycin outside of Yugoslavia, Czechoslovakia, or release by Pfizer. Dr. Bruni speculated that since they are quite close in structure, clarithromycin might be used to treat infections which are reported to have responded to azithromycin.

Clarithromycin is available in the U.S. through the PWA Health Group in New York City; the drug is expensive, and two to four weeks are required to obtain it from abroad. Requests must include a doctor's prescription; interested people can call 212/532-0280 to ask for a mail-order form.

Clarithromycin may be available immediately from a new buyers club in Los Angeles, called LABC/Staying Alive; their number is 213/748-1295. Both of these groups are non-profit organizations, run by people well known in the community.

One aspect of the clarithromycin research plans challenged by ACT UP/New York's Treatment and Data Committee is the decision of Abbott Laboratories to test clarithromycin alone against MAI, since clinical experience with treating mycobacterial infections generally has concluded that a multiple drug approach is necessary.

Proprietary interests could explain the single-agent focus, and yet if an effective drug fails to win results because of an ineffective application, no one's interests will be served. Trials implementing different approaches could be conducted at the same time, and should be soon, given the critical passage of time for people now ill.

On the other hand, high marks were given to Abbott's plans to design a trial of clarithromycin as a possible prophylaxis against several infections at once. The compassionate release of azithromycin for toxoplasmosis is a welcome gesture from Pfizer. Both Abbott and Pfizer have in their possession substances which at the moment may be the best, or only, options for treating many people. Whether these drugs are approved for lesser infections or continue on to larger studies, the only appropriate pace is one of urgency.

References

1. McCabe RE and Oster S. Current recommendations and future prospects in the treatment of toxoplasmosis. Drugs, volume 38, number 6, pages 973-987, December 1989.

2. Girard AE, Cimochowski CR, and Faiella JA. Correlation of increased azithromycin levels with phagocyte infiltration into sites of infection [abstract 762]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 21-24, 1990, Atlanta.

3. Wildfeur A, Laufen H, Muller-Wening D, and Haferkamp O. Interaction of azithromycin and human phagocytic cells. Uptake of the antibiotic and the effect on the survival of ingested bacteria in phagocytes. Arzneimittelfurschung, volume 39, number 7, pages 755-758, July 1989.

4. Bermudez LE, Young LS. Activities of amikacin, roxithromycin, and azithromycin alone or in combination with tumor necrosis factor against Mycobacterium avium complex. Antimicrobial Agents and Chemotherapy, volume 32, number 8, pages 1149-1153, August, 1988.

5. Dautzenberg B, Legris S, Truffot C, and others. Clarithromycin clears Mycobacterium Avium Intracellulare (MAIC) from blood of AIDS patients. A randomized trial [abstract 1264]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 21-24, 1990, Atlanta.

6. Prokocimer P, Dellerson M, Craft C, Pernet A, Ruff B, and Grosset J. Effect of clarithromycin on blood cultures positive for Mycobacterium Avium Complex in HIV+ patients [abstract 634]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 21-24, 1990, Atlanta.

7. Pichotta P, Gupta S, Prokocimer P, and Pernet A. The overall safety of oral clarithromycin in comparative clinical studies [abstract 1332]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 21-24, 1990, Atlanta.

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