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Published in the Bulletin of Experimental Treatments for AIDS April 1998 issue, by the San Francisco AIDS Foundation. |
Drug Watch: Nitazoxanide for Cryptosporidial DiarrheaMark Bowers The treatment of cryptosporidiosis -- infection of the lining of the intestine with the parasite Cryptosporidium parvum, found in contaminated food and water -- has until recently focused primarily on controlling the main symptom: watery diarrhea, as frequently as 20 times a day. Cryptosporidiosis is found in 10-20% of people with AIDS who have significant diarrhea. No satisfactory effective therapy existed to treat the infection until nitazoxanide was clinically studied. Nitazoxanide (brand name NTZ) is an antihelminthic drug that has been available for several years in developing countries where tapeworm and liver fluke infestations are common. The drug is not yet approved for human use in the U.S., but the U.S. manufacturer, Unimed Pharmaceuticals, submitted a New Drug Application on December 30, 1997 to the Food and Drug Administration (FDA) to market nitazoxanide for diarrhea associated with cryptosporidiosis. Nitazoxanide is more familiar and more widely used by physicians in Texas than elsewhere in the U.S. because patients there have comparatively easy access to Mexican pharmacies, where Mexican manufactured nitazoxanide is available by prescription. Cryptosporidiosis is familiar to physicians throughout the nation as a result of massive outbreaks traced to contaminated water supplies in Las Vegas and Milwaukee. The 1993 Milwaukee incident resulted in more than 400,000 cases, and more than 100 people with AIDS died as a result. An estimated 45 million people may be exposed to cryptosporidium each year through municipal water systems. Clinical ResultsClinical studies in Mali and Mexico looked at people taking 500 mg of nitazoxanide twice a day. A 30-person U.S. study conducted by Rosemary Soave, MD, of Cornell University Medical College compared increasingly larger doses of nitazoxanide, beginning with 500 mg/day for 2 weeks, increased to 1,000 mg/day for 2 weeks, then 1,500 mg/day, 2,000 mg/day and, in some cases, 3,000 mg/day. Measurements of the effectiveness of the treatment were stool frequency and presence or absence of oocysts (parasite eggs) in stool samples. For this study, a complete response was 3 or fewer bowel movements per day, while a decrease of 50% or greater was considered a partial response. For 28 study participants who could be evaluated, the 500 mg/day dose was found to be ineffective; 57% of study participants responded to therapy at 1,000 mg/day and some study participants who took a dose of at least 1,000 mg/day experienced a parasitological cure. Unimed Pharmaceuticals designed an expanded access program that created more data to present to FDA for marketing approval. Nitazoxanide was offered through independent physicians for a total of 70 clinical study sites around the U.S. Eight weeks of case report forms were submitted and parasitology exams were performed for 139 participants who received nitazoxanide. Responses to the drug were defined differently than in the study led by Soave. Here, a 50% reduction in the number of bowel movements was considered a complete response, while a 25-49% reduction was considered a partial response. After 8 weeks on the drug, 35% reported complete responses and another 23% reported partial responses. In real terms, the average number of stools at the beginning of the study was 7-8 per day. By the end of 8 weeks, this was reduced to 3 per day. Because of the open-label study design, there were cryptosporidium oocysts in the stool of only 39 participants. Participants in the study kept symptom logs in which they recorded the incidence of diarrhea, rectal urgency, weight loss or gain, ability to work a full day and other measures. Improvements were noticed in all self-reported measurements In an unusual move, FDA has allowed Unimed to submit historical data from other studies rather than conduct an additional placebo-controlled study. Data from AIDS Clinical Trials Group (ACTG) study 192 established that people's diarrhea responded to treatment with a placebo about 30% of the time. In contrast, most physicians independently polled suggest a placebo response rate closer to 10 or 15%, and nearly all of the participants who reportedly responded to placebo in ACTG 192 were enrolled at the same study site. This suggests that something besides a genuine response to placebo, as measured by a substantial reduction in the frequency of bowel movements, may eventually explain this unusually high placebo response rate. Unimed has further analyzed the data from 14 people who initially responded to nitazoxanide then relapsed when they stopped taking the drug. These individuals experienced a 50% response rate when they were once again given nitazoxanide, which suggested that people do not easily develop tolerance to the drug. In parallel to this finding, 5 people who had an initial partial response to nitazoxanide and then discontinued the drug all became complete responders when given nitazoxanide again. The Best DoseThe combined experience of the participants in the above studies suggests that people should start taking nitazoxanide at 1,000 mg/day (one 500 mg pill twice a day) for 4 weeks, then increase the dose if necessary to 2,000 mg/day. Unimed has asked for this labeling in the FDA official language for the drug. Some study participants have been on open-label nitazoxanide for more than 1 year, suggesting that dosing may continue indefinitely. Side EffectsSide effects due to nitazoxanide are rare. They include increased values in certain liver function tests, scleral yellowing (the sclera is the white of the eye), urine that is intensely yellow, urticaria (hives) that can be treated with antihistamines without discontinuing the use of nitazoxanide. One study participant reported fluorescent green ejaculate (it is not known whether he took large doses of B vitamins). What Needs to be DoneDrug interaction studies have not yet been done. Of particular interest are possible interactions with hormonally based birth control drugs because of nitazoxanide's effect on glucuronide. The pharmacokinetics of the drug are well characterized. About one-third of the drug is absorbed into the body, and most of it is eliminated unchanged. Probably the drug is effective because of its penetration of the lumen, the interior surface of the intestine, the site of infection with cryptosporidium. Certainly other parasites that are killed by the drug are exposed to nitazoxanide because of its presence where they live, not because the drug reaches particular effective levels in the blood. What are Other TreatmentsMany people who have started taking combination anti-HIV therapy including a protease inhibitor have seen a resolution of the symptoms of microsporidiosis and cryptosporidiosis in addition to increased CD4 cell counts, decreased viral loads, weight gain and cessation of reliance on antidiarrheal and antimicrobial agents. There are those who do not respond well to combination therapy, those whose regimens have failed them and those who do not choose to take them. Each of these groups of individuals remains at risk for active infection. The current standard for treating cryptosporidiosis is based on anecdotal evidence that paramomycin (Humatin) at 2-4grams per day in divided doses reduces stool frequency. However, clinical studies did not prove that the drug was more effective than placebo. Azithromycin, roxithromycin, optim and Sporidin-G, an oral antibody preparation obtained from cryptosporidium-infected cows, have all been studied. Sporidin-G may be effective in up to 50% of those treated. Janssen Pharmaceuticals cancelled clinical studies of diclazuril and letrazuril due to poor efficacy. In the absence of effective treatments, prevention through avoiding the organism itself has been stressed. Certain water filters and bottled water, careful washing and peeling or cooking of fruits and vegetables, and avoidance of risky sexual practices involving oral-anal contact have all been repeatedly stressed for those at risk (see BETA, March 1996, pages 33-36). It is preferable to avoid re-exposure even after successfully eliminating cryptosporidiosis once. According to the February 4, 1998 issue of Journal of the American Medical Association, data collected from 10 large cohorts of HIV positive people strongly suggest that people with CD4 cell counts less than 75 cells/mm3 who took clarithromycin (Biaxin) or rifabutin (Mycobutin) to prevent Mycobacterium avium complex (MAC) disease also effectively prevented cryptosporidiosis. Where Else can Nitazoxanide be of Use?Clinical studies in tropical Africa have yielded very positive results against cryptosporidiosis and infection with several other organisms, including Isospora belli, Entamoeba histolytica, Giardia lamblia, Ascaris lumbricoides, Enterobius vermicularis, Hymenopsis nana and Dicrocoelium dentriticum. Nitazoxanide is under study for microsporidiosis, another intestinal infection for which no effective treatment has yet been found. Drug Availability
Mark Bowers is Managing Editor of Treatment Publications at the San Francisco AIDS Foundation.
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