THE OI REPORT: A Critical Review of the Treatment & Prophylaxis of AIDS-Related Opportunistic Infections (OIs)

CRYPTOSPORIDIOSIS
by Laura Morrison

MICROBIOLOGY & EPIDEMIOLOGY
Cryptosporidium is a small, obligate, intracellular protozoan that occurs widely in nature and causes disease in animals and humans. While many species of Cryptosporidium have been identified, only two, Cryptosporidium parvum and Cryptosporidium muris, are known to infect mammals (Upton 1985). Cryptosporidia are highly infectious and can be transmitted through water, food, animal-to-human and human-to-human contact. Because of Cryptosporidia's ubiquity and ease of transmission, people with compromised immune systems should take special precautions to avoid exposure, which are outlined in the prevention section later in this chapter.

Although there are no definitive data on the prevalence of cryptosporidiosis in people with AIDS, an estimated 10-15% of people with AIDS (PWAs) in the U.S. and 30-50% of those in developing countries may develop the disease (Petersen 1992). The U.S. Centers for Disease Control and Prevention (CDC) estimates that 5-10% of PWAs per year develop cryptosporidiosis (CDC 1995).

Roberts and colleagues conducted a cross-sectional study of HIV-infected New York City residents to determine the prevalence of cryptosporidial infection. 397 subjects were interviewed, from 375 (94%) of whom serum samples and from 317 (80%) of whom stool samples were obtained. While just four (1.3%) of stool samples were positive for C. parvum, 21/120 (18.5%) of serum specimens had anti C. parvum antibodies (Roberts 1997).

Manabe and colleagues carried out a case-control chart review of 88 HIV-infected patients with cryptosporidiosis and corrleated this with histopathologic review of 32 patients from whom gastrointestinal (GI) biopsies were conducted. 86% of the patients had another AIDS-defining illness at the time of diagnosis. The investigators identified four distinct clinical syndromes - chronic diarrhea (37%), relapsing illness (14%), cholera-like disease (33%) and disease which resolved (16%). African Americans and injecting drug users had a shorter mean survival from diagnosis (p<0.03). Clinical category of cryptosporidiosis did not appear to affect outcome. Acquisition of cryptosporidiosis was associated with Candida esophagitis (OR=2.53, p<0.02) and white race (OR=6.71, p<0.01) but not sexual orientation. Cases survived significantly less long than controls (277 vs. 424 days, p<0.01). Antiretroviral drug use, regardless of CD4 count, appeared protective (OR=0.07, p<0.01). Patients with cholera-like or relapsing disease were more likely to have had upper and lower GI biopsies, and in these patients, cryptosporidial organisms were identified throughout the gut (Manabe 1997).

CLINICAL MANIFESTATIONS
Human cryptosporidiosis is generally caused by C. parvum, and its primary clinical manifestation is profuse, watery, non-bloody diarrhea. Other symptoms include abdominal pain and cramping, nausea, vomiting and weight loss. Immunocompetent humans may contract cryptosporidiosis, but they are able to rid themselves of the disease within a short period even without treatment. There are three types of clinical presentations of cryptosporidiosis in persons with HIV infection: transient or acute disease, which lasts less than 28 days (typically in persons with CD4 counts greater than 200); chronic disease, with diarrhea lasting more than 28 days; and fulminant disease, with greater than or equal to 20 stools a day. It is not known how frequently these types of presentations occur in PWAs.

Fever is generally absent in intestinal cryptosporidiosis. If a person with HIV has both a fever and diarrhea, or a mycobacterial infection such as Mycobacterium avium complex (MAC), are more likely the cause (Nelson 1992). Nelson and colleagues note that bacterial causes of diarrhea are typically missed in stool cultures and recommend that patients with fever as well as diarrhea have blood cultures performed to determine if there is a bacterial cause, such as MAC (Nelson 1992). Nevertheless, fever can be a symptom of biliary cryptosporidiosis, which may affect 15% to 25% of PWAs who have intestinal cryptosporidiosis (Rosemary Soave, personal communication). Symptoms of biliary cryptosporidiosis are like those of cholangitis: right upper quadrant pain, nausea and vomiting, and fever. Unfortunately, biliary cryptosporidiosis cannot be diagnosed conclusively without invasive procedures and the lack of any effective treatment calls into question the value of such methods. Once a safe, effective, and well-absorbed treatment is found for intestinal cryptosporidiosis, ought to be effective in the biliary tree too.

DIAGNOSIS
When cryptosporidiosis was first seen in humans in the late 1970s, diagnosis required an intestinal biopsy. Since 1981, numerous easy and reliable diagnostic techniques for identifying Cryptosporidium oocysts in feces have been developed. These include variations of modified acid-fast stain, fluorescent auramine-rhodamine stain, ELISA antigen capture methods and indirect immunofluorescent assay (IFA). It was also determined early on that using concentration techniques such as Sheather's sugar cover-slip flotation and Formalin-ethyl acetate sedimentation before staining could increase the odds of identifying small numbers of Cryptosporidium oocysts in the stool (Garcia 1983; Ma 1983). So much progress had been made in Cryptosporidium diagnosis that by 1986 Rosemary Soave and Donald Armstrong wrote, "There is a general consensus that regardless of the [fecal] staining method applied, experienced observers have little difficulty in identifying oocysts" (Soave 1986).

Nonetheless, diagnosis of intestinal cryptosporidiosis remains a problem. Very few labs routinely look for the organism, thus many lab technicians are not experienced in testing for and identifying Cryptosporidium. There is also a disinclination on the part of hospitals and insurers to pay for ELISA or indirect fluorescent antibody tests, which, though more sensitive than acid-fast stains, are also more expensive. Acid-fast stains, while generally reliable and easy to interpret (Cryptosporidium oocysts stain bright red; yeasts stain green), are not sensitive and fail to detect Cryptosporidium when there are fewer than 100,000 organisms in a formed stool or 10,000 in a watery stool (Weber 1991). In cases where a modified acid-fast stain fails to detect oocysts and the symptoms persist, a more sensitive, expensive test is warranted.

PROPHYLAXIS
There is no known prophylaxis for cryptosporidiosis, however, a recent study of people with AIDS being given prophylaxis for M. avium complex (MAC) suggests that rifabutin and clarithromycin may also prevent the onset of cryptosporidiosis (Holmberg 1997). Holmberg and colleagues analyzed data from 1019 patients with HIV and fewer than 75 CD4 cells who were seen at 10 sites from 1992 to 1996. Among those who took clarithromycin or rifabutin for MAC prophylaxis, a significantly smaller percentage developed cryptosporidiosis compared to those who did not take those agents. A relatively small number of patients who took azithromycin for MAC prophylaxis did not see a decreased incidence of cryptosporidiosis. More research must be done into the prophylactic effect of these agents against cryptosporidiosis.

TREATMENT
Despite ten years of clinical trials, there is still no FDA-approved therapy and no standard of care for the treatment of cryptosporidiosis. Efforts to find useful therapies have been impeded by the absence of an in vitro model and the lack of a universally accepted animal model with which to screen potential agents (Soave 1990). The parasitology laboratory in the Division of Biology, Kansas State University has developed a 96-well ELISA for rapid screening of pharmaceuticals for anti-cryptosporidial activity. In 1995, the laboratory studied over 150 drugs for activity against Cryptosporidium in vitro (Upton 1997).

Dozens of pharmacological and immunomodulating agents have been tried in humans, some of which have appeared at least marginally effective for some portion of the affected population -- though a placebo effect may well explain some reports of apparent temporary efficacy. Other drugs are currently being researched.

Spiramycin
One of the agents tested for anti-cryptosporidiosis activity early in the AIDS epidemic was the macrolide antibiotic spiramycin, which was used in Europe and Canada against the protozoan Toxoplasma gondii. Initial anecdotal reports were encouraging enough for the FDA's Division of Anti-infective Drug Products to make spiramcyin available to physicians on a compassionate use basis for cryptosporidiosis in PWAs. The CDC received reports on 13 patients with AIDS and cryptosporidiosis at a number of institutions who received 1 gram (gm) of spiramycin 3 or 4 times daily. After 3 to 4 weeks of therapy, 3 of the 13 were completely cured (symptoms improved, stool exams and intestinal biopsies negative), and they remained asymptomatic for 6 to 7 months after stopping therapy. Another 3 patients had improvement in symptoms but continued to have the parasite in their stools. All 3 of these patients saw their symptoms recur after stopping therapy. The remaining 7 had no response (MMWR 1984).

Moskovitz and colleagues treated 47 immunosuppressed patients with spiramycin 1 g three times a day (Moskovitz 1988). Of the 37 who were evaluable, 28 had a favorable response (at least a 50% reduction in baseline bowel movements and fewer than five bowel movements a day) and 9 had no response. Twelve of the 28 who had a favorable response also cleared the parasite; 7 within four weeks of treatment and 5 within eight weeks of treatment. Sixteen patients with symptomatic improvement but did not clear the parasite were maintained indefinitely on spiramycin. Six patients discontinued spiramycin due to adverse events, including gastrointestinal symptoms, elevated liver function and leukopenia. Most were receiving concomitant medications.

Not all published reports of spiramycin for the treatment of cryptosporidiosis were positive (Woolf 1987). Soave conducted a randomized, double-blind, placebo-controlled trial in 73 AIDS patients of 3 million units of spiramycin three times a day for three weeks. No difference was noted between the drug and placebo. Subsequent pharmacokinetic studies suggested that poor absorption of spiramycin may have impacted that finding (Soave, personal communication). Due to concerns that oral spiramycin is poorly absorbed, the AIDS Clinical Trials Group undertook ACTG 113, a placebo-controlled, multi-center safety and efficacy trial of intravenous (IV) spiramycin for cryptosporidiosis, testing doses of 3 million units and 4.5 million units. Five of 31 patients had met criteria for clinical and parasitological improvement, while 16 achieved a partial response. Although there was a statistically significant drop in Cryptosporidium counts in the stools of those who received drug versus placebo, IV spiramycin had toxicities including paresthesia, nausea, vomiting, and at high doses, severe colitis (Rosemary Soave, personal communication).

Diclazuril and Letrazuril
Diclazuril is a benzene acetonitrile derivative that was first studied for cryptosporidiosis because of its activity against the related protozoan parasite Eimeria. In 1989, a dose-escalating Phase I/II placebo-controlled study found that the drug was poorly absorbed and generally ineffective. Only at the highest dose (800 mg a day) were significant diclazuril serum levels achieved. Patients who achieved significant serum levels were the only responders (Soave 1990).

Letrazuril, a more bioavailable analog of diclazuril, was later tested by the ACTG in a randomized, double-blind, placebo-controlled, multi-center trial (ACTG 198). Letrazuril, taken orally, was found to be well absorbed and appeared to eradicate the parasite when stools samples were examined by acid-fast staining. The lack of significant reduction in diarrhea among patients on active drug, however, led researchers to reexamine the stool smears using ELISA antigen capture methods and the indirect immunofluorescent assay. In fact, stool samples that were negative by the acid-fast method were positive using the other methods, leading investigators to conclude that letrazuril does not kill Cryptosporidium, but rather affects the acid-fast staining pattern (Rosemary Soave, personal communication).

A recently published open-label study of letrazuril in 35 patients with AIDS-related cryptosporidiosis documented a complete clinical response in only one patient. Twenty-two patients had a partial response defined as a "greater than 50% reduction in bowel movements per day for at least one week." Fifteen (69%) of the responses were short-lived, suggesting that the patients may have experienced a placebo effect (Loeb 1995). This placebo effect, common in cryptosporidiosis, testifies to the power of a patient's own belief that a treatment may be efficacious, whether or not it really is, and is manifested in double-blind trials when patients on placebo experience symptomatic relief. Thus, to determine efficacy of marginally active drugs, the proportion of patients responding symptomatically on placebo must be compared with those responding on drug.

Octreotide (Sandostatin™, Sandoz)
Octreotide is a longer-lasting analogue of somatostatin, a naturally-occuring secretory peptide in the gastrointestinal tract, which has shown efficacy against secretory diarrheas caused by pancreatic cholera syndrome and carcinoid tumors. Several anecdotal reports in the late 1980s suggested that somatostatin may be beneficial in the treatment of AIDS-related cryptosporidiosis (Cook 1988; Katz 1988; Clotet 1989). A study of octreotide in people with AIDS-related diarrhea revealed that the drug appeared to be more effective in people without identifiable pathogens rather than those with Cryptosporidium or other identifiable pathogens. Cello and colleagues treated 51 people with AIDS and diarrhea with escalating doses of subcutaneous octreotide ranging from 50 to 500 mg three times a day according to response. Of 15 patients with Cryptosporidium in stool or small-bowel biopsy, only 5 had a reduction in daily stool volume. 14 of 23 patients with no identifiable pathogen at baseline responded to octreotide (Cello 1991).

Romeu and colleagues saw slightly better results with octreotide in a similar dose-escalating study of 29 patients with AIDS-associated diarrhea. Twenty-one patients had confirmed cryptosporidiosis at baseline. Patients were treated with 50 to 500 mg thrice daily with subcutaneous octreotide. Of the 18 evaluable patients with cryptosporidiosis, 4 had a complete response (bowel movements decreased to two or fewer per day with an increased stool consistency), and 9 had a partial response (50% reduction in daily bowel movements and/or increased stool consistency). Six of 7 non-cryptosporidial patients had a complete response to octreotide therapy while one had no response (Romeu 1991). Octreotide is generally not used for the treatment of cryptosporidiosis because published non-controlled data has been mediocre and because it is expensive and inconvenient to administer.

Antiretroviral Therapy
In the late 1980s, several case reports noted significant responses in AIDS patients with cryptosporidiosis after treatment with AZT. Connolly and colleagues reported on three AIDS patients with cryptosporidiosis who eliminated their diarrhea and the parasite after receiving AZT (Connolly 1988). The authors theorized that the patient's clinical and parasitic resolution was due to the improvement in immune function caused by AZT rather than any direct anticryptosporidial activity of the drug. Many researchers agree with this conclusion. A later study of 47 HIV-positive patients with cryptosporidiosis established a correlation between immune function and ability to limit the disease. All of those with 180 CD4 cells or more were able to overcome the disease without treatment within a month, while 87% with fewer than 140 CD4 cells developed persistent disease (Flanigan 1992).

Three reports presented in early 1997 suggest that the improved immune function brought about by protease inhibitors helps people clear cryptosporidiosis.

In a study of patients with cryptosporidiosis and microsporidiosis, Carr and colleagues treated five patients with cryptosporidial diarrhea with combination antiretroviral therapy including a protease inhibitor (Carr 1997). All five patients saw their symptoms improve within 12 weeks and have since stopped taking all pain killers and anti-diarrheals. None have relapsed.

In another study, Benhamou and colleagues evaluated fifteen patients with chronic cryptosporidiosis (n=9) or microsporidiosis (n=6) who had been taking triple antiretroviral therapy including either Crixivan (Indinavir™, Merck) or Norvir (Ritonavir™, Abbott) for a mean time of 3.8+/-1.4 months (Benhamou 1997). All nine patients with cryptosporidiosis revealed no identifiable parasites in multiple stool examinations, and diarrhea resolved for 12 patients.

Mileno and collegues reported a case in which they gave Crixivan (Indinavir™, Merck) to a man who had 33 CD4 cells and who had cryptosporidiosis for six months (Mileno 1997). The man's symptoms cleared and three stool samples were negative for Cryptosporidium oocysts.

There is considerable hope that the newer, more potent antiretroviral drug regimens available now will be effective for even more people with cryptosporidiosis.

Azithromycin (Zithromax™, Pfizer)
Azithromycin is a macrolide antibiotic approved by the FDA in 1992 for the treatment of bacterial infections and approved in 1996 for the prevention of Mycobacterium avium complex (MAC) in people with advanced HIV infection. On the basis of the activity of spiramycin and other macrolides on Cryptosporidium, azithromycin was studied for anticryptosporidial activity, first in animal models and then in humans. In a multi-center, placebo-controlled, double-blind study of azithromycin for AIDS-related cryptosporidial diarrhea, 80 patients were randomized to receive either 900 mg of azithromycin a day or placebo for three weeks. At the end of three weeks, patients on drug were switched to azithromycin at 300 mg a day for three weeks and those on placebo received azithromycin at 900 mg a day. A preliminary analysis of the first three weeks documented a non-statistically significant trend in reduction in bowel movements and weight loss among those in the treatment arm. Among the 33 participants for whom serum azithromycin levels were obtained, there was a significant correlation between serum azithromycin levels and decreased oocyst shedding. The authors concluded that the data supported continued study (Soave 1993). Soave has subsequently conducted as yet unpublished studies of oral azithromycin (dose ranging from 900 to 1800 mg/day) and IV azithromycin (in five very sick patients with severe cryptosporidial diarrhea).

According to Soave, azithromycin may have a role in cryptosporidiosis treatment in the absence of a fully effective therapy. She cautions that patients with cryptosporidiosis should take the lactose-free formulation available via compassionate use from Pfizer (1-800-742-3029) rather than the generally available formulation. She also notes that it may take as long as a month to see an effect with azithromycin and it must be given in high doses. Soave treats patients with 1200 mg (four 300 mg tablets) once a day. Most patients seem to tolerate the high-dose, perhaps because absorption of the drug is low.

Hyperimmune Bovine Colostrum
Hyperimmune bovine colostrum is derived from the milk of post-natal cows who were immunized with Cryptosporidium oocysts during their pregnancy, generating anti-Cryptosporidium antibodies. Since the late 1980s, there have been numerous anecdotal reports on hyperimmune bovine colostrum for treatment of cryptosporidiosis in immune-compromised patients (Tzipori 1986; Saxon 1987; Tzipori 1987; Unger 1990; Sluiters 1994). Some patients had no improvement of symptoms or parasite burden (Saxon 1987), while others had complete cessation of diarrhea (Tzipori 1987) and parasite shedding (Unger 1990).

In 1990, Nord and colleagues conducted a double-blind study of hyperimmune bovine colostrum versus bovine colostrum with no anticryptosporidial antibodies in five patients with AIDS-related cryptosporidiosis. The colostrum was administered continuously via nasogastric tube at 20 millimeter per hour for 10 days, with three of the five patients receiving active colostrum. Two of the 3 patients on active colostrum saw reduction in stool volume, more formed stools and excreted a lower concentration of oocysts after treatment, while the third showed no improvement. Both control patients had a decrease in diarrhea volume after infusion with the non-immune colostrum, but no net decrease in oocysts shed. The colostrum infusion caused side effects in four of the five patients: nausea and vomiting in three and abdominal cramps in a fourth. The researchers recommended that future hyperimmune bovine colostrum products be more practical to administer and have higher titers of anticryptosporidial antibodies (Nord 1990).

In 1994 Fries and colleagues reported on two randomized, multicenter trials of oral Bovine anti-Cryptosporidium Immunoglobulin (BACI) for treatment of cryptosporidiosis in PWAs. In the first trial, 40 patients received either 20 g (grams) of BACI a day or placebo for one week followed by a week of open-label BACI 20 g a day . There was no significant difference in stool frequency or volume between the two groups, although those who had received 2 weeks of drug had a lower median oocyst count in the second week of treatment. In the second trial, 20 patients received one week of BACI at 20 g aday followed by a week at 40 g a day and a week at 80 g a day for as long as diarrhea persisted and the doses were well tolerated. Among 13 patients whose dose was escalated above 20 g a day, mean and median oocyst counts declined and 7 of 13 post-treatment stools had oocyst counts below the level of detection versus 1 of 13 pre-treatment stools. There was no effect on stool volume or frequency (Fries 1994).

GalaGen Inc. is now enrolling patients in a placebo-controlled, multi-center efficacy trial of bovine immunoglobulin concentrate-C. parvum, a drinkable version of hyperimmune bovine colostrum that is said to taste better and has a 34% greater concentration of anticryptosporidial antibodies than previous versions. Ninety patients will be randomized to receive either drug or placebo for 28 days, after which all patients will be eligible to receive drug for 8 weeks. Results of a 24-patient study of bovine immunoglobulin concentrate C. parvum in 24 people with AIDS and diarrhea suggest that the powdered form of the drug is both a well tolerated and promising therapy for people with AIDS-related cryptosporidial diarrhea (Greenberg 1996). More information about GalaGen's current trial is available by calling 1-800-372-AIDS.IGX-CP (Hyperimmune Egg Yolks)

IGX-CP (Hyperimmune Egg Yolks)
IGX-CP is an experimental oral formulation of egg yolks from chickens immunized with Cryptosporidium antigen. An open-label safety and efficacy pilot study was started in 1994. Twenty-four patients were given 60 mL five times a day for 3 weeks. 25-30% of participants had a reduction in diarrhea, although not in parasite. Five patients had to discontinue therapy because they could not tolerate the fat and cholesterol. If the manufacturer could increase the immunoglobulin and reduce the fat in IGX-CP it might merit further study (Rosemary Soave, personal communication).

Paromomycin (Humatin)
Paromomycin (Humatin) is a poorly absorbed aminoglycoside antibiotic approved in the U.S. for treatment of amebiasis. Because numerous case reports suggest its efficacy, it is currently prescribed by many clinicians as first-line therapy for cryptosporidiosis. Nonetheless, there is a lack of controlled data indicating its effectiveness for most people with the disease. While paromomycin apparently limits the manifestations of cryptosporidiosis in some patients, most do not eliminate the parasite. On the basis of a report at the Sixth International Conference on AIDS that suggested paromomycin controlled cryptosporidial diarrhea in some patients (Gathe 1990), Clezy and colleagues embarked on a 5 patient study with paromomycin for the treatment of HIV-related cryptosporidiosis (Clezy 1990). Patients weighing over 60 kg were given 2 g of paromomycin daily while those who weighed under 60 kg were given 1.5 gm daily. Patients were on drug for 4 to 8 weeks. Four patients noted a significant reduction in diarrhea within 24 hours of beginning therapy and the fifth saw a similar reduction within one week. All reported increased appetite and sense of well being, but only one patient cleared the parasite.

Fichtenbaum and colleagues, citing recent evidence of paromomycin's in vitro activity against Cryptosporidium (Marshall 1992), treated seven cryptosporidiosis patients with 500 mg of paromomycin every 6 hours. Six of 7 were also taking antiretroviral therapy and antidiarrheal agents. All seven saw a reduction in diarrhea within 1 to 5 days of beginning therapy; six were able to stop taking other antidiarrheals entirely and the remaining patient reduced his use of them. Two patients, however, relapsed while on paromomycin (one after 3 months and the other after 4) and three had their symptoms recur after stopping therapy (Ficthenbaum 1993).

In 1994, White and colleagues reported a 70% response rate in 10 patients in a prospective, double-blind trial of paromomycin for the treatment of cryptosporidiosis (White 1994). In 1996, Flanigan and colleagues reported that 48% of 44 patients in a prospective, single-arm, multicenter trail of paromomycin, 500 mg four times a day for four weeks, saw improvement or resolution of diarrhea (Flanigan 1996).

ACTG 192 enrolled 35 patients in a multi-center, double-blind, placebo-controlled study of paromomycin for the treatment of cryptosporidiosis (Hewitt 1997). For 21 days 17 patients were given 500 mg paromomycin qid while 18 were given placebo. Four of the patients on placebo did not complete the full three weeks of therapy and thus were not evaluable. At the end of the third week, there was no statistically significant difference in clinical or parasitologic response between the two groups.

(Hewitt 1997)

Almost one-third of patients in the placebo arm improved spontaneously, suggesting that this study may have evaluated significant numbers of persons with transient disease, which complicates analysis of any medication.

Nitazoxanide (NTZ)
Nitazonxanide (NTZ) is a nitrothiazole benzamide compound with antimicrobial activity against an array of protozoan, helminthic and bacterial pathogens. Preclinical studies have shown anti-cryptosporidial activity in vitro and researchers are hopeful that it will show similar activity in humans. A clinical efficacy study of NTZ in 24 AIDS patients with severe cryptosporidiosis or other intestinal protozoan infections was conducted in Mali. The patients received 500 mg of NTZ twice a day for 7 days. Of the 15 patients with cryptosporidiosis, 64% had negative fecal examinations on days 7 and 14 following initial treatment. 78% of the patients had their diarrhea resolve or improve after treatment (Unimed Pharmaceuticals, Inc., 1995).

Another efficacy study of NTZ for people with AIDS-related cryptosporidial diarrhea was conducted in Mexico (Feregrino 1996). Fifteen adult patients with chronic diarrhea who had failed on other therapies received either 500 mg or 1000 mg NTZ twice a day for between 10 and 30 days. All patients had a parasitic response with negative biopsy and stool culture and 11 had resolution of their diarrhea. The four patients who continued to have diarrhea tested positive for salmonella and cytomegalovirus, which could account for their continued symptoms.

In the United States, an open-label safety, efficacy, and pharmacokinetic study comparing four doses of NTZ (500 mg, 1000 mg, 1500 mg and 2000 mg a day) enrolled 30 people with AIDS and cryptosporidiosis (Davis 1996). Analysis of 28 patients who had received at least 4 weeks of drug showed that 56% had a reduction in bowel movement frequency and 31% saw a reduction in parasite, with 18% clearing the parasite from their stools. Higher doses of NTZ were well tolerated and appeared to correlate with higher levels of NTZ and its metabolites in the blood. One investigator said that there was no evidence of a more favorable response at higher doses, perhaps because there were too few people in each arm, and perhaps because people in the 1500 mg arm were severely ill (Rosemary Soave, personal communication). ACTG 336 will enroll 60 subjects in a multicenter, double-blind, placebo-controlled study of NTZ for people with AIDS and cryptosporidiosis. Participants will receive NTZ 1000 mg twice a day or placebo for the first 21 days. After day 21, all patients will be given active drug. Those who respond to NTZ will be randomized onto one of two maintenance doses after 42 days on the drug. To find out about sites in your area, call the AIDS Clinical Trials Information Service at 1-800-TRIALS-A.

PREVENTION
Awareness among the HIV/AIDS community of the risk of Cryptosporidium transmission has been heightened in recent years, particularly since public water supplies have been recognized as sources of cryptosporidial infection (Hayes 1989, MacKenzie 1994). There is no consensus among public health professionals or AIDS advocates as to whether people with compromised immune systems should adjust their lifestyles to limit the risk of Cryptosporidium infection. Some argue that exposure to Cryptosporidium is difficult to avoid. Others note that many asymptomatic people already carry the parasite. In light of the fact that cryptosporidiosis is a painful, devastating, and potentially incurable opportunistic infection, TAG strongly urges immunosuppressed people to consider taking measures to avoid exposure. Because of potential contamination of public drinking water, it would be prudent for people with HIV and fewer than 200 CD4 cells should boil tap water for at least 1 minute or run it through a one micron filter before using it to drink, brush their teeth or wash food. Either of these methods will kill the Cryptosporidium oocysts. Prices for one micron filters that attach to faucets start at around $50. Drinking bottled water is an option for those who can afford it, but not all brands are guaranteed Cryptosporidium-free. When eating out, avoid consuming unfiltered drinking water, ice made from unfiltered water, and raw fruits and vegetables washed in unfiltered water. The CDC's "Question and Answer Fact Sheet on Cryptosporidiosis" lists the following steps that immunosuppressed people should take to avoid infection with Cryptosporidium: avoid drinking untreated surface water directly from lakes or streams; avoid swimming in lakes or municipal pool frequented by large groups of diaper-aged children; avoid sexual practices resulting in exposure to feces (e.g., rimming); avoid contact with feces of all animals, particularly young farm animals such as calves; wash your hands thoroughly after any contact with young animals or with soil (e.g., gardening), or after changing diapers.

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