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Brief Report |

Possible Effectiveness of Clarithromycin and Rifabutin for Cryptosporidiosis Chemoprophylaxis in HIV Disease FREE

Scott D. Holmberg, MD, MPH; Anne C. Moorman, BSN, MPH; Jennifer C. Von Bargen; Frank J. Palella, MD; Mark O. Loveless, MD; Douglas J. Ward, MD; Thomas R. Navin, MD; for the HIV Outpatient Study (HOPS) Investigators
[+] Author Affiliations

From the Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention (Dr Holmberg and Mss Moorman and Von Bargen), and the Division of Parasitic Diseases, National Center for Infectious Diseases (Dr Navin), Centers for Disease Control and Prevention, Atlanta, Ga; Northwestern University Medical School, Chicago, Ill (Dr Palella); and Oregon Health Sciences University, Portland (Dr Loveless). Dr Ward is in private practice in Washington, DC.


JAMA. 1998;279(5):384-386. doi:10.1001/jama.279.5.384.
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Published online

Context.— Cryptosporidium parvum infection, a common cause of diarrhea in persons infected with the human immunodeficiency virus (HIV), is difficult to treat or prevent.

Objective.— To evaluate relative rates of cryptosporidiosis in HIV-infected patients who were either receiving or not receiving chemoprophylaxis or treatment for Mycobacterium avium complex.

Design.— Analysis of prospectively collected data from HIV-infected patients' visits to their physicians since 1992.

Setting.— Ten (8 private, 2 publicly funded) HIV clinics in 9 US cities.

Patients.— A total of 1019 HIV-infected patients with CD4+ cell counts less than 0.075×109/L.

Main Outcome Measures.— Incidence of clinical cryptosporidiosis during treatment with clarithromycin, rifabutin, and azithromycin.

Results.— Five of the 312 patients reportedly taking clarithromycin developed cryptosporidiosis vs 30 of the 707 patients not taking clarithromycin (relative hazard [RH], 0.25 [95% confidence interval (CI), 0.10-0.67]; P =.004).Two of the 214 patients taking rifabutin developed cryptosporidiosis vs 33 of the 805 not taking rifabutin (RH, 0.15 [95% CI, 0.04-0.62]; P=.01). Prophylactic efficacy of either drug was 75% or greater. No protective effect was seen in the 54 patients reportedly taking azithromycin (RH, 1.48 [95% CI, 0.44-5.04]; P=.46).

Conclusions.— Clarithromycin and rifabutin were highly protective against development of cryptosporidiosis in immune-suppressed HIV-infected persons in this analysis; further study is warranted.

CRYPTOSPORIDIUM PARVUM is a serious cause of opportunistic infection in persons with the human immunodeficiency virus (HIV), yet chemoprophylaxis or treatment for it with about 100 antimicrobial agents has remained discouraging or inconclusive.1,2 For example, therapeutic efficacy of spiramycin or paromomycin has been difficult to demonstrate in small clinical trials.1,3,4 Newer semisynthetic macrolide antibiotics, such as clarithromycin and azithromycin, have shown promise in small therapeutic trials, but cryptosporidiosis has been a life-threatening illness for an estimated 10% to 15% of patients with the acquired immunodeficiency syndrome in the United States.1,2

Based on a report indicating that none of 63 HIV-infected persons reportedly taking 500 mg of clarithromycin twice a day developed cryptosporidiosis vs 4 (5.5%) of 73 patients without the drug (not statistically significant),5 we were prompted to assess cryptosporidiosis risk in those taking or not taking Mycobacterium avium complex (MAC) chemoprophylaxis or treatment in the HIV Outpatient Study (HOPS).

HOPS is an actively recruiting cohort that now includes over 2800 HIV-infected out-of-hospital patients seen in about 30000 symptom-driven visits since 1992. Study sites include 10 (8 private and 2 public) clinics caring for HIV-infected patients. HOPS physicians are almost all board certified in both internal medicine and infectious disease and care for HIV-infected patients only.

Information in 5 categories—demographics and risk behaviors for HIV infection; symptoms; diagnosed diseases ("definitive" and "presumptive"); medications taken (dose and duration); and laboratory test results—is abstracted at each visit, electronically entered at each site using a common form, collected centrally, and reviewed and corrected before entry in the Centers for Disease Control and Prevention database. This analysis includes patients seen up to April 1996. Much effort has been applied to the correctness and completeness of HOPS data, including standardized training and extensive verifying of data.

Because we aimed to investigate those receiving clarithromycin and other MAC prophylaxis (azithromycin or rifabutin) who were also at risk for clinical cryptosporidiosis,6 we limited this analysis to HOPS patients with CD4+ cell counts less than 0.075×109/L. We considered that a person had taken 1 of the 3 drugs if reportedly taking it for at least 3 months continuously. The period of patient observation was time between first clinic visit when CD4+ cell count was less than 0.075×109/L until last clinic visit (before April 1996) or development of cryptosporidiosis. Outcome measure was clinical cryptosporidiosis, defined as diarrhea and other gastrointestinal symptoms, leading to a physician visit, with a positive stool examination for C parvum oocysts (acid-fast staining of unconcentrated fecal smears). We analyzed effects of drugs of interest, demographic and socioeconomic variables, and other factors, notably observation duration and most recent CD4+ cell count, on outcome.

Data were analyzed with Statistical Analysis Software (SAS Institute Inc, Cary, NC), version 6.11. Incidence density of cryptosporidiosis, incidence relative risk, confidence intervals, and P values were calculated using maximum likelihood (likelihood ratio) tests. Potentially confounding variables were analyzed by continuity-adjusted χ2, Wilcoxon rank sum, and Fisher exact (2-tailed) tests.

A time-dependent accelerated failure time analysis,7 using SAS PROC LIFEREG, version 6.11, was done to assess relative contributions of individual drugs and independent (demographic and immunologic) variables to the likelihood of developing disease.

A change-in-estimate forward stepwise method was used to assess importance and order of independent variables entered into the final model.8 A variable that changed the estimate of association between a MAC drug and cryptosporidiosis by 5% or more was considered a potential confounder. The variable that changed the association the most, and by at least 5%, was put in the model, and remaining variables were added one at a time. When no new variable changed the association estimate by more than 5%, the model was considered complete.8

We identified 535 HIV-infected patients who had taken clarithromycin, azithromycin, or rifabutin for 5546 patient-months of observation and 484 patients not receiving these drugs and who were followed up for 4510 patient-months (Table 1); all patients had CD4+ cell counts less than 0.075×109/L. Patients taking these drugs had a mean of 13.6 (range, 2-66) visits and those not taking them had a mean of 7.9 (range, 2-46) visits. Those taking any of the 3 drugs usually did so for prophylaxis (77%) vs therapy for MAC (17%); 6% took any drug or a combination for both prophylaxis and treatment of MAC.

Table Graphic Jump LocationTable 1.—Characteristics of Patients With CD4+ Cell Counts Less Than 0.075×109/L by Mycobacterium avium Complex Prophylaxis and Treatment*

The 535 patients reportedly taking MAC drugs and the 484 persons not taking them were comparable in many ways (Table 1). Men who have sex with men were better educated, more likely to have a private medical payment source, and more likely to receive drugs (and earlier) than other groups. These variables, among others, were considered potentially confounding and so included in the final statistical model.

We evaluated outcomes after and histories of cryptosporidiosis and diarrhea before each patient observation. The 1019 patients had the following dispositions over about 312 years of data collection: 458 (45%) were still actively being followed by April 1, 1996; 353 (35%) died—without cryptosporidiosis diagnosis—while under care; 76 (8%) were transferred; 74 (7.3%) were "inactive"; 38 (3.7%) had no clinic visit for more than 6 months as of April 1, 1996; and 20 (2%) could not be located. Prior to the censoring date of observation (first CD4+ cell count <0.075×109/L), 2 (0.4%) of 484 patients with information of the 535 (later receiving MAC drugs) and 2 (0.5%) of 385 patients of the 484 (later not receiving them) were known to have had cryptosporidiosis; 61 (12.6%) of the 484 of those not taking the drugs and 55 (10.3%) of the 535 taking MAC drugs reported diarrhea. No difference was statistically significant.

There were no differences in most recent cell count between those taking vs those not taking any drug (0.038 vs 0.039×109/L), nor any drug individually: clarithromycin (0.040 vs 0.038×109/L); rifabutin (both, 0.039×109/L); or azithromycin (0.038 vs 0.039×109/L).

A statistically significant protective effect against cryptosporidiosis in those taking clarithromycin or rifabutin was seen, and it remained significant in a time-dependent accelerated failure regression model that controlled for age, sex, race, transmission risk category, source of medical payment, CD4+ cell count, and use of the other 2 MAC drugs (Table 2). Prophylactic efficacy of either drug—calculated as (1−relative hazard)—was 75% or greater. However, no observed protective effect was seen for the few patients on azithromycin.

Table Graphic Jump LocationTable 2.—Occurrence of Cryptosporidiosis in HIV-infected HOPS Patients With CD4+ Cell Counts Less Than 0.075×109/L by Mycobacterium avium Complex Prophylaxis and Treatment*

We could not confirm drug adherence in the 9 persons receiving MAC chemoprophylaxis who developed cryptosporidiosis, since 7 had died; however, 1 patient who died had a history of nonadherence with other drug regimens. Prescribed drug dosage was generally higher (except 1 case) in those not developing cryptosporidiosis than in those developing it, although the numbers are too small for meaningful statistical analysis (data not shown).

This analysis indicates that those reportedly on MAC prophylaxis with clarithromycin or rifabutin also had a several-fold decreased risk of developing cryptosporidiosis, a statistically robust effect in regression analyses controlling for observation duration and many demographic (age, sex, race, transmission risk group, main source of medical payment) and immunologic (CD4+ cell count) variables. We did not find statistically significant differences in several possible confounders, such as geographic site (municipal water source9) and drugs considered unrelated to development of cryptosporidiosis (acyclovir and trimethoprim-sulfamethoxazole), that might be indexes of access to medical care (data not shown).

There are unavoidable limitations; these data were derived from an observed cohort, not a controlled clinical trial, and unmeasured factors may confound associations. The 3 drugs, recommended in HIV patients only for prevention and treatment of MAC,10 may have been differentially prescribed and used by HIV patients in this study. However, patients who did and did not receive MAC drugs did not differ markedly in demographic or immunologic profiles (Table 1), and our analyses controlled for these variables and others. Because we lacked an absolute standard or another commonly used test for Cryptosporidium infection, we do not know if some patients taking macrolides had suppressed and undetectable stool organisms, yet suffered from cryptosporidiosis. Still, only a high rate of "false-negative" stool examination results—and that occurring in persons suffering from disease despite undetectable stool C parvum oocytes—would negate the large and robust prophylactic efficacy of clarithromycin and rifabutin seen.

Of factors possibly confounding the observed protective effect, host immunologic function is putatively most important. Cryptosporidial diarrhea is less likely in those with high or increasing CD4+ cell counts.11,12 Besides limiting our analyses to those with a CD4+ cell count of less than 0.075×109/L, the time-dependent regression model controlled for this factor. Also, means of most recent CD4+ cell counts of those with or without MAC prophylaxis or treatment were both about 0.040×109/L. Thus, no confounding variable—such as combination antiretroviral or protease inhibitor use (not approved for use or available generally until after periods of observation in this analysis)—was detected that would enhance immunologic protection.

Data regarding biologic mechanisms and efficacy of these drugs are relatively scant and inconclusive. Some semisynthetic macrolides may reduce cryptosporidial oocyst load in stools of infected persons13,14: clarithromycin and azithromycin activity against Cryptosporidium has been seen in vitro and in experimental models.2 Lower activity of clarithromycin vs azithromycin in animal models15,16 may result from animal inability to produce the active 14-hydroxy-metabolite seen in humans receiving clarithromycin. A few controlled trials of clarithromycin and azithromycin in treating cryptosporidiosis in about 90 patients have shown decreased stool oocytes and some clinical benefit.17 anecdotal reports of success with spiramycin, another macrolide antibiotic, indicate possible benefit in placebo-controlled trials in 54 patients with acquired immunodeficiency syndrome.3,18

We are unaware of animal models or human trials of rifabutin anticryptosporidial activity, a semisynthetic ansamycin antibiotic with a mechanism of action distinct from that of macrolides. Although there may be few or no published studies of rifabutin in treating cryptosporidiosis, a possible protective effect should be considered.

The lack of protective effect in those taking azithromycin is confusing, since it is similar in structure and action to clarithromycin and spiramycin, which seem to have some therapeutic efficacy in animals and humans.13 Therapeutic efficacy of a 500-mg daily dose of azithromycin, however, was not seen in a recent study.19 The lack of prophylactic efficacy seen in our data may partly be attributable to small numbers of patients receiving azithromycin (54 persons), of whom only 2 developed cryptosporidiosis and who may not have been adherent. The small numbers preclude a definitive conclusion about its potential utility.

Randomized clinical trials of this issue will be difficult, as study participants with low CD4+ cell counts cannot ethically be randomized for MAC chemoprophylaxis, and newer antiretroviral therapy will confound the analysis.

We found robust and statistically significant protective effects of clarithromycin and rifabutin, used for MAC prophylaxis and treatment, in preventing cryptosporidiosis. These data, primarily involving chemoprophylaxis, cannot necessarily be extended to treatment of HIV-infected persons with cryptosporidiosis. We conclude that similar analyses of other data sets and expanded trials of new macrolide and other agents for preventing cryptosporidiosis in HIV-infected persons are warranted.

Petersen C. Cryptosporidiosis in patients with the human immunodeficiency virus.  Clin Infect Dis.1992;15:903-909.
Ritchie DJ, Becker ES. Update on the management of intestinal cryptosporidiosis in AIDS.  Ann Pharmacother.1994;28:767-768.
Flanigan TP, Soave R. Cryptosporidiosis.  Prog Clin Parasitol.1993;3:1-20.
White Jr AC, Chappell CL, Hayat CS, Kimball KT, Flanigan TP, Goodgame RW. Paromomycin for cryptosporidiosis in AIDS: a prospective, double-blind trial.  J Infect Dis.1994;170:419-424.
Jordan W. Clarithromycin prophylaxis against Cryptosporidium enteritis in patients with AIDS.  J Natl Med Assoc.1996;88:425-427.
Flanigan T, Whalen C, Turner J.  et al.  Cryptosporidium infection and CD4 counts.  Ann Intern Med.1992;116:840-842.
Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data.  New York, NY: John Wiley & Sons; 1980.
Hosmer DW, Lemeshow S. Applied Logistic Regression.  New York, NY: John Wiley & Sons; 1989:66-68.
Centers for Disease Control and Prevention.  Assessment of inadequately filtered public drinking water—Washington, DC, December 1993.  MMWR Morb Mortal Wkly Rep.1994;43:661-663, 669.
Centers for Disease Control and Prevention.  1997 USPHS-IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus.  MMWR Morb Mortal Wkly Rep.1997;46(RR-12):1-46.
Crowe SM, Carlin JB, Stewart KI, Lucas CR, Hoy JF. Predictive value of CD4 lymphocyte numbers for the development of opportunistic infections and malignancies in HIV-infected persons.  J Acquir Immune Defic Syndr.1991;4:770-776.
McGowan I, Hawkins AS, Weller IV. The natural history of cryptosporidial diarrhoea in HIV-infected patients.  AIDS.1993;7:349-354.
Di Bari MA, Bonavita B, Costigliola P.  et al.  Intestinal and disseminated cryptosporidiosis in AIDS patients. In: Program and abstracts of the XI International Conference on AIDS; July 7-12, 1996; Vancouver, British Columbia. Abstract ThA 4061.
Giacometti A, Cirioni O, Del Prete SM.  et al.  In-vitro anti-cryptosporidial activity of macrolides alone and in combination with other drugs. In: Program and abstracts of the 36th Interscience Conference of Antimicrobial Agents and Chemotherapy; September 15-18, 1996; Washington, DC. Abstract E70.
Rehg JE. Anticryptosporidial activity of macrolides in immunosuppressed rats.  J Protozool.1991;38(suppl):147S.
Fayer R, Ellis W. Glycoside antibiotics alone and combined with tetracyclines for prophylaxis of experimental cryptosporidiosis in neonatal balb/c mice.  J Parasitol.1993;79:553-558.
Blagburn BL, Soave R. Prophylaxis and chemotherapy: human and animal. In: Cryptosporidium and Cryptosporidiosis. Boca Raton, Fla: CRC Press Inc; 1997:113-130.
Portnoy D, Whiteside ME, Buckley III E, MacLeod CL. Treatment of intestinal cryptosporidiosis with spiramycin.  Ann Intern Med.1984;101(suppl):202-204.
Blanshard C, Shanson DC, Gazzard BG. Pilot studies of azithromycin, letrazuril and paromomycin in the treatment of cryptosporidiosis.  Int J STD AIDS.1997;8:124-129.

Figures

Tables

Table Graphic Jump LocationTable 1.—Characteristics of Patients With CD4+ Cell Counts Less Than 0.075×109/L by Mycobacterium avium Complex Prophylaxis and Treatment*
Table Graphic Jump LocationTable 2.—Occurrence of Cryptosporidiosis in HIV-infected HOPS Patients With CD4+ Cell Counts Less Than 0.075×109/L by Mycobacterium avium Complex Prophylaxis and Treatment*

References

Petersen C. Cryptosporidiosis in patients with the human immunodeficiency virus.  Clin Infect Dis.1992;15:903-909.
Ritchie DJ, Becker ES. Update on the management of intestinal cryptosporidiosis in AIDS.  Ann Pharmacother.1994;28:767-768.
Flanigan TP, Soave R. Cryptosporidiosis.  Prog Clin Parasitol.1993;3:1-20.
White Jr AC, Chappell CL, Hayat CS, Kimball KT, Flanigan TP, Goodgame RW. Paromomycin for cryptosporidiosis in AIDS: a prospective, double-blind trial.  J Infect Dis.1994;170:419-424.
Jordan W. Clarithromycin prophylaxis against Cryptosporidium enteritis in patients with AIDS.  J Natl Med Assoc.1996;88:425-427.
Flanigan T, Whalen C, Turner J.  et al.  Cryptosporidium infection and CD4 counts.  Ann Intern Med.1992;116:840-842.
Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data.  New York, NY: John Wiley & Sons; 1980.
Hosmer DW, Lemeshow S. Applied Logistic Regression.  New York, NY: John Wiley & Sons; 1989:66-68.
Centers for Disease Control and Prevention.  Assessment of inadequately filtered public drinking water—Washington, DC, December 1993.  MMWR Morb Mortal Wkly Rep.1994;43:661-663, 669.
Centers for Disease Control and Prevention.  1997 USPHS-IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus.  MMWR Morb Mortal Wkly Rep.1997;46(RR-12):1-46.
Crowe SM, Carlin JB, Stewart KI, Lucas CR, Hoy JF. Predictive value of CD4 lymphocyte numbers for the development of opportunistic infections and malignancies in HIV-infected persons.  J Acquir Immune Defic Syndr.1991;4:770-776.
McGowan I, Hawkins AS, Weller IV. The natural history of cryptosporidial diarrhoea in HIV-infected patients.  AIDS.1993;7:349-354.
Di Bari MA, Bonavita B, Costigliola P.  et al.  Intestinal and disseminated cryptosporidiosis in AIDS patients. In: Program and abstracts of the XI International Conference on AIDS; July 7-12, 1996; Vancouver, British Columbia. Abstract ThA 4061.
Giacometti A, Cirioni O, Del Prete SM.  et al.  In-vitro anti-cryptosporidial activity of macrolides alone and in combination with other drugs. In: Program and abstracts of the 36th Interscience Conference of Antimicrobial Agents and Chemotherapy; September 15-18, 1996; Washington, DC. Abstract E70.
Rehg JE. Anticryptosporidial activity of macrolides in immunosuppressed rats.  J Protozool.1991;38(suppl):147S.
Fayer R, Ellis W. Glycoside antibiotics alone and combined with tetracyclines for prophylaxis of experimental cryptosporidiosis in neonatal balb/c mice.  J Parasitol.1993;79:553-558.
Blagburn BL, Soave R. Prophylaxis and chemotherapy: human and animal. In: Cryptosporidium and Cryptosporidiosis. Boca Raton, Fla: CRC Press Inc; 1997:113-130.
Portnoy D, Whiteside ME, Buckley III E, MacLeod CL. Treatment of intestinal cryptosporidiosis with spiramycin.  Ann Intern Med.1984;101(suppl):202-204.
Blanshard C, Shanson DC, Gazzard BG. Pilot studies of azithromycin, letrazuril and paromomycin in the treatment of cryptosporidiosis.  Int J STD AIDS.1997;8:124-129.
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