AIDS TREATMENT NEWS #224, JUNE 2, 1995

Saccharomyces boulardii is a live yeast widely used in Europe and elsewhere to treat diarrhea; millions of doses are sold each year. Recently, with increasing interest in using it for HIV-related diarrhea, this potential treatment has become one of the top sellers at some AIDS buyers' clubs, including Healing Alternatives in San Francisco, and the PWA Health Group in New York.

A number of published clinical trials (almost all in HIV- negative persons) have reported apparent usefulness in preventing or treating diarrhea resulting from various causes. No one knows how S. boulardii may work, however. It does NOT seem to kill diarrhea-causing organisms directly; instead, it may reduce inflammation in the gut, or increase certain immune responses in the blood. (The latter theory might explain how one study found S. boulardii may have been modestly useful for treating acne, even though the yeast did not leave the intestinal tract.) HIV-Related Research Little research has been done with S. boulardii in persons with HIV. In 1990, French researchers reported on 30 patients who had four to eight liters of watery stools per day for at least three months. When they were given three grams per day of S. boulardii, "fecal output decreased to less than one liter per day after 48 hours of treatment, and eight days after the onset of the drug, stools were fully formed."(1) The following year, the same research team reported on improvement in 17 patients with HIV and diarrhea; in 12 of them, the cause of the diarrhea could not be diagnosed. The average number of stools decreased from 9 to 2.1 per day in 15 days, and there was an average weight gain of 8 kg (17.7 lbs).(2) Neither of these reports were from controlled trials, however.

In 1992 French researchers reported the results of a placebo- controlled trial of S. boulardii, in 36 patients with AIDS- related diarrhea which -- importantly -- was not responsive to any attempt to treat any known cause of the diarrhea.(3) On entry into the trial, their average age was 34.8 years, and their average weight was 58.7 kg (130 lbs). Thirty five of the 36 patients completed the study. At the end of the trial, 10 of 18 patients who received S. boulardii were diarrhea free, vs. only 1 of 17 who received the placebo -- a difference which is highly statistically significant. Also, the treatment group gained 2.0 kg (4.2 lbs), while the placebo group lost 3.1 kg (6.85 lbs); this difference is also statistically significant. The length of the trial was not stated in the abstract. As far as we know, this is the only completed controlled trial of S. boulardii in persons with HIV.

The latest medical article anywhere on S. boulardii in HIV- related diarrhea was published in 1993; it is a case report of a successful treatment.(4) (Unfortunately, one major computer database mis-translated the German title into English as "Saccharomyces boulardii Therapy of HIV Associated Failures," instead of "Saccharomyces boulardii Therapy of HIV Associated Diarrhea," giving a completely wrong impression of the article. But the MEDLINE database generally used in the U.S. does have the correct translation of the title.) Until recently, 26 persons with HIV were being studied in controlled clinical trials in Seattle. During the first two weeks, some were randomly assigned to receive a placebo. Then everyone received the drug in decreasing doses, to help define the safest and most effective maintenance dose. Unfortunately, this trial was recently stopped -- for business reasons, not because of any problem with the treatment. (The sponsor decided to focus on another trial, testing S. boulardii with antibiotics to prevent recurring Clostridium difficile diarrhea; all the persons in that trial must be HIV negative. That study may be finished by the end of 1995; with luck, S. boulardii could be approved for preventing C. difficile recurrences in about two years.) S. boulardii appears to be quite safe; no serious adverse effects have been found in any clinical trial. But one theoretical danger is that this yeast could take advantage of an immune deficiency and cause a systemic infection. Only two cases of this have been reported, out of perhaps more than a million people who have used the treatment since it was first used for diarrhea in the 1950s. Both were probably HIV- negative (neither had been tested, but neither was being treated for anything HIV related); both previously had serious intestinal problems which may have allowed the yeast to leave the intestine and enter the bloodstream. Both cases were successfully treated with amphotericin B, a powerful antifungal.

Clinical Trials for Other Diseases McFarland and Bernasconi(5) reviewed controlled trials studying S. boulardii for treatment or prevention of diarrhea due to various causes not related to HIV. All the results reported below -- from studies they reviewed, and also from more recent reports -- are from controlled trials, and are statistically significant.

Three large trials studied S. boulardii for prevention of antibiotic-associated diarrhea.(6,7,8) This condition can occur as a side effect of certain antibiotics, which can kill beneficial organisms in the gut and thus allow an overgrowth of disease-causing organisms which are normally kept under control. In all three of the trials, S. boulardii reduced the incidence of diarrhea by at least 50 percent.

Two other controlled studies showed that S. boulardii treatment caused about a two-fold or three-fold reduction in diarrhea caused by feeding with a nasogastric tube.(9,10) S. boulardii, used with certain antibiotics, has also been studied for treating C. difficile, a serious intestinal infection. After several positive case reports and uncontrolled studies, a major placebo-controlled trial found that S. boulardii plus antibiotics prevented recurrences of C. difficile better than the antibiotics alone,(11) but this could only be established for patients with a history of recurrences; for those with their initial C. difficile infection, the difference between the treatment and placebo groups was not statistically significant. (This failure to reach statistical significance does not mean that S. boulardii failed to help in these cases, however; "because of the small numbers of patients with initial CDD who failed, there was only a 10% power of detecting a significant difference; therefore, the result could be a type II error."(11)) A study in a few patients with Crohn's disease also found statistically significant benefit of S. boulardii in reducing diarrhea.(12) Researchers in Austria tested S. boulardii in 3,000 healthy volunteers for prevention of travelers diarrhea. They gave a small dose (250 mg per day), a moderate dose (1 gram per day) or a placebo to persons about to travel to distant regions. Those who received the treatment, especially the higher dose, were significantly less likely to get diarrhea.(13) Studies of S. boulardii for treating ordinary diarrhea in children(14,15) have shown significant benefit. And in a trial in adults,(16) the treated group did not have a significant reduction in the number of stools, but it did have a lower proportion of watery stools.

S. boulardii does not remain in the intestine after use is stopped, but is eliminated from the body within several days.(5) Research findings differ on whether the yeast needs to be alive when taken. Even dead yeast may cause some of the effects which have been observed.

Note: A number of laboratory studies, animal studies, and uncontrolled human trials, NOT involving HIV in any way, have suggested that S. boulardii might be helpful in treating specific kinds of diarrhea or other illnesses. In this article, we have not reviewed or referenced those studies. Instead, we have focused on all HIV studies, and on placebo- controlled human trials for any condition.

Availability Today At least two different S. boulardii products are available in AIDS buyers' clubs today.

Laboratoires Biocodex, the French company now running clinical trials of S. boulardii, markets a lyophilized (freeze-dried) form of the yeast in Europe, South America, and Africa, but not in the U.S. It is sold under different brand names (Ultra-Levure(tm), Thiemann(tm), Perenterol(tm), Floratil(tm)) in different countries. This product is available from the PWA Health Group, the largest AIDS buyers' club in New York (212/255-0520). The three-gram per day dose used in trials for AIDS-related diarrhea is moderately expensive; at the PWA Health Group, a four-day supply costs $36. Biocodex has been selling S. boulardii since 1962.

A competing product sold by Jarrow Formulas is less expensive; but whether the two products are equivalent is controversial. The PWA Health Group only carries the Biocodex version; while Healing Alternatives, the major AIDS buyers' club in San Francisco, carries only the Jarrow brand; both can ship the product anywhere within the U.S. Some health- food stores also sell the Jarrow brand.

With the Biocodex product, each 250-mg capsule is formulated to contain one billion live yeasts, when tested six months or more after manufacture. According to Biocodex, their in-house testing, which has not previously been published, has shown that there can be as much as a two log (99 percent) drop in the number of live yeasts in the month after manufacture. According to Jarrow Rogovin, president of Jarrow Formulas, this does not happen if the capsules are refrigerated.

With the Jarrow product, each 310-mg capsule is formulated to contain at least 500 million live yeasts when manufactured; it may contain more.

We believe that what is most important is to find out whether or not S. boulardii may be helpful for you -- and that the best way to do this is to try a test with the more established Biocodex product, starting with three grams a day (twelve 250-mg capsules) for at least a week, and preferably for two weeks. (You might want to order additional supply, to avoid running out if it does seem to work.) After this test, if you decide to continue with S. boulardii, you might be able to reduce the cost by reducing the dose, and/or switching to the Jarrow product, to see if a less expensive regimen works as well for you.

How S. boulardii Is Used Because of the lack of scientific studies of S. boulardii for persons with HIV, information on how to use this treatment is highly anecdotal and imprecise, and sometimes contradictory.

According to at least one of the buyers' clubs, most people using S. boulardii for HIV-related diarrhea start with 3 grams a day, and then work down to 1 gram a day if that is sufficient to keep the diarrhea controlled. Most people divide the dose into two or three portions, and take the capsules with a glass of water after eating. (One recommendation we have seen says two hours after meals; another just says after eating.) Some people take a gram a day or less "for gut regulation or stomach aches," even without diarrhea. According to the PWA Health Group, there are no known drug incompatibilities, although it has been suggested that if fluconazole maintenance is being used, the two treatments should not be taken at the same time, so that the fluconazole will be less likely to kill the yeast.

How many people have used S. boulardii for HIV-related diarrhea? No one knows; the PWA Health Group estimates that maybe a few hundred people have tried it; and they have received only one report of a suspected side effect, a rash. Healing Alternatives was selling about 90 bottles a month before a recent article in a gay newspaper in San Francisco increased demand. It has only heard one anecdotal report that the treatment did not work; all the other reports have been positive, even with severe diarrhea. (Readers should keep in mind, however, that negative results are usually the least likely to be reported; the treatment is probably not working as well as the existence of so few negative reports might suggest.) Perhaps the most serious safety concern with S. boulardii is that appropriate medical care could be delayed, if people treat themselves for diarrhea without first getting medical attention so that the underlying cause of the problem can be diagnosed and treated, when possible. People should remember that the HIV-related medical studies cited above were done with patients whose diarrhea either could not be diagnosed, or could not be treated by standard means. In many cases, standard medical care cannot help; this is why new treatments are needed. But failure to use available therapy for a treatable condition, such as CMV infection, could lead to serious harm.

The Future So far there has been very little study of use of S. boulardii for treating AIDS-related diarrheas. We have heard that a trial is being conducted in Germany; as far as we know, this is the only study anywhere of S. boulardii in persons with HIV. Biocodex may study it again for HIV diarrhea sometime in the future, but probably not until the development for C. difficile is complete. It would be very difficult for anyone to conduct a legal, U.S. study of S. boulardii independently of Biocodex, either using its product, or any other; collaboration might be possible, however.

Sally Cooper, executive director of the PWA Health Group in New York, informally outlined some research directions she would like to see, in a private communication to AIDS TREATMENT NEWS on May 30, 1995: "Things I'd like to see followed up: use in kids with HIV -- what a great thing to have a safe intervention for kids, who have wicked diarrhea all the time, and there have been at least two studies in non-HIV kids; amoebas (also a small number of promising abstracts, much gentler than Flagyl and even tinidazole, again safe for kids); various stomach ailments; thrush and preventing the spread of thrush (as per animal studies). 80% of the lymph is in the gut, so things that work specifically in the gut, like S. boulardii and ketotifen, seem especially interesting. Both are theorized (and shown in people with ketotifen, but only in animals with S. boulardii) to improve and maintain mucosal membrane health in the gut. And people gain weight -- seems like more than just stopping up the system. I suspect it might be an excellent maintenance therapy for PWAs with low CD4 counts, or anyone starting a major course of antibiotics, especially clindamycin." [Note: tinidazole and ketotifen are drugs which are approved in some countries but not in the U.S., and are used by people with AIDS.] The bad news is that none of this research is likely to start for years; who would pay for it? But the good news is that a great many people have used S. boulardii, and some people have used it for AIDS-related diarrhea over the last several years; from all we know at this time, the treatment appears to be exceptionally safe.

The other good news is that if S. boulardii is going to work, it works quickly, usually greatly reducing diarrhea within a week or two. A short test should be enough to see if it is going to work for you. If not, little has been lost. And if the treatment does work, then the financial cost, and the small, largely theoretical risk of serious side effects, may be worth accepting.

References 1. Saint-Marc T, Sellem C, Rosello L, and Touraine JL. Treatment of chronic diarrhea with Saccharomyces boulardii. Sixth International Conference on AIDS, San Francisco, June 20-24, 1990 [abstract #Th.B.363].

2. Saint-Marc T, Rossello-Prats L, and Touraine JL. Efficacite de Saccharomyces boulardii dans le traitement des diarrhees du SIDA. ANNALES DE MEDECINE INTERNE. 1991; volume 142, number 1, pages 64-65.

3. Blehaut H, Saint-Marc T, and Touraine JL. Double blind trial of Saccharomyces boulardii in AIDS related diarrhea. Submitted to the Eighth International Conference on AIDS, Amsterdam, 1992, but not published in the conference abstracts.

4. Born P, Lersch C, Zimmerhackl B, and Classen M. Saccharomyces-boulardii therapie HIV-assoziierter durchfalle. DTSCH. MED. WOCHENSCHR. 1993; volume 118, number 20, page 765.

5. McFarland LV and Bernasconi P. Saccharomyces boulardii: A Review of an Innovative Biotherapeutic Agent. MICROBIAL ECOLOGY IN HEALTH AND DISEASE. 1993; volume 6, pages 157-171.

6. Adam J, Barret A, Barret-Bellet C, and others. Essais cliniques controles en double insu de l'ultra-levure lyophilisee. Etude multicentrique par 25 medecins de 388 cas. GAZETTE MEDICALE DE FRANCE. 1977; volume 84, pages 2072-2078.

7. Surawicz CM, Elmer GW, Speelman P, McFarland LV, Chinn J, and Van Belle G. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study. GASTROENTEROLOGY. 1989; volume 96, pages 981-988.

8. McFarland LV, Surawicz CM, Greenberg RN, and others. Prevention of beta-lactam-associated diarrhea by Saccharomyces boulardii compared with placebo. THE AMERICAN JOURNAL OF GASTROENTEROLOGY. 1995; volume 90, number 3, pages 439-448.

9. Tempe JD, Steidel AL, Blehaut H, Hasselmann M, Lutun PH, and Maurier F. Prevention par Saccharomyces boulardii des diarrhees de l'alimentation enterale a debit continu. LA SEMAINE DES HOPITAUX DE PARIS. 1983; volume 59, pages 1409- 1412.

10. Schlotterer M, Bernasconi P, Lebreton F, and Wassermann D. Interet de Saccharomyces boulardii dans la tolerance digestive de la nutrition enteral a debit continu chez le brule. NUTRITION CLINIQUE ET METABOLISME. 1987; volume 1, pages 31-34.

11. McFarland LV, Surawicz CM, Greenberg RN, and others. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA. 1994; volume 271, number 24, pages 1913-1918.

12. Plein K, and Holtz J. Therapeutic effects of Saccharomyces boulardii on mild residual symptoms in a stable phase of Crohn's disease with special respect to chronic diarrhea -- a pilot study. Z. GASTROENTEROL. (Germany). 1993; volume 31, number 2, pages 129-134.

13. Kollaritsch H, Holst H, Grobara P, and Wiedermann G. Prevention of traveler's diarrhea with Saccharomyces boulardii. Results of a placebo controlled double-blind study. [English translation of the title.] FORTSCHR MED. 1993; volume 111, number 9, pages 152-156.

14. Chapoy P. Traitement des diarrhees aigues infantiles: essai controle de Saccharomyces boulardii. ANNALES DE PEDIATRIE 1985; volume 32, pages 561-563.

15. Cetina-Sauri G and Basto GS. Evaluacion terapeutica de Saccharomyces boulardii en ninos con diarrea aguda. TRIBUNA MEDICA. 1989; volume 56, pages 111-115.

16. Hochter W, Chase D, and Hagenhoff G. Saccharomyces boulardii bei akuter erwachsenendiarrhoe. MUNCHENER MEDIZINISCHE WOCHENSCHRIFT. 1990; volume 132, pages 188-192.