Hewitt, Ross G.; Papandonatos, George D.; Shelton, Mark J.; Hsiao, Chiu-Bin; Harmon, Barbara J.; Kaczmarek, Sharon R.; Amsterdam, Daniel
In the absence of antiretroviral therapy, disseminated Mycobacterium avium complex (dMAC) infection was a common opportunistic infection in patients with advanced HIV disease, occurring in 15 to 40% of patients within 2 years of a diagnosis of AIDS [1-3]. A dMAC infection results in fever, weakness, chills, night sweats, diarrhea, weight loss, and abdominal pain . Anemia and thrombocytopenia are common. Among patients with AIDS, those with untreated dMAC infection have a shorter survival compared with those without the infection [5,6].
Clarithromycin (500mg orally twice daily), azithromycin (1200mg orally weekly) and rifabutin (300mg orally daily) when given as single agent prophylaxis all significantly reduce the incidence of dMAC infection [7-9]. Each of these agents has in vitro activity against M. avium complex (MAC) [10-12]. Clarithromycin and rifabutin also prolong survival in AIDS patients [9,13]. However, all three agents are associated with gastrointestinal side effects.
The dose of clarithromycin indicated for the treatment of dMAC bacteremia is identical to the dose currently recommended for prophylaxis. The dose of rifabutin and clarithromycin (in selected patients) is recommended to be reduced with concurrent use of HIV protease inhibitors . Once daily, reduced dose clarithromycin, if effective, could lower the cost of MAC prophylaxis and lessen potential drug interactions; consequently, the effectiveness of once daily, reduced dose clarithromycin to prevent dMAC infection in patients with advanced HIV disease was compared with rifabutin or no prophylaxis.
This study was conducted at a single urban municipal medical center. Through a clinical database, the outpatient medical records of adult HIV-1-seropositive patients for whom CD4 cell counts remained <100¥106 cells/l during the period 1 January 1991 to 1 January 1997 were selected for review. Patients were prescribed oral daily clarithromycin 500mg or oral rifabutin 300mg. The choice of regimen was that of the patient and his or her primary care physician. Because the study began when the practice of chemoprophylaxis for MAC was not routine, there were patients who had no MAC prophylaxis prescribed.
To be included in the study population, patients had to have been observed for at least 90 days with no positive blood cultures for dMAC and had no CD4 count rise above 100¥106 cells/l at any time during the study period. Patients were considered to have received study prophylaxis if they received clarithromycin for at least 30 consecutive days. Patients were considered to have received control prophylaxis if they received rifabutin for at least 30 consecutive days. Patients were considered not to have received prophylaxis if neither of these agents nor any alternative MAC prophylaxis regimen was prescribed.
Adherence to clarithromycin and rifabutin therapy was assessed by chart review. Patients were considered to be adherent if there was evidence of the following: their prescriptions were refilled on a regular basis, patients self-reported adherence to clarithromycin or rifabutin to nursing or medical staff, or home care nurses reported good adherence to clarithromycin or rifabutin.
Patients were excluded if they received alternative forms of MAC prophylaxis, including azithromycin for more than 30 consecutive days; participated in ACTG 196 (a clinical dMAC prevention study of twice daily clarithromycin versus high-dose rifabutin versus the combination); or received clarithromycin 500mg twice daily or a dose other than 500mg every day. Patients were also excluded if their chart was unavailable, there was incomplete documentation of MAC prophylaxis, there were no surveillance mycobacterial blood cultures, or the patient was judged to be non-adherent to therapy. In addition, patients were excluded if they received treatment for tuberculosis or other mycobacterial infection (not dMAC), had dMAC at baseline or developed another non-tuberculous infection other than dMAC.
Study endpoints were the development of a positive blood culture for MAC, prescription of an HIV-1 protease inhibitor, voluntary change of medical care from the study site, or death. All patients who developed dMAC were treated with a combination regimen that contained clarithromycin. The length of the observation period was defined as the time in days from the date of the first visit to the date of the last visit within the dates 1 January 1991 and 1 January 1997.
CD4 cell counts, liver transaminases (alanine and aspartate, ALT, AST), renal function tests (serum blood urea nitrogen, creatinine), hepatitis B core antibody and hepatitis C antibody measurements, mycobacterial culture results, and mycobacterial resistance measurements were recorded. CD4 cell counts were determined by flow cytometry. Mycobacterial cultures of the blood were obtained from patients at the start of prophylaxis and periodically during prophylaxis (approximately every 6 months) or earlier if signs and symptoms of dMAC disease were present. Mycobacterial cultures were performed with the BACTEC system using a previously described method . Mycobacterial susceptibility assays for clarithromycin and rifabutin were performed using a modification of a broth dilution technique . The antiretroviral treatment history, type of prophylaxis for Pneumocystis carinii infection, purified protein derivative (PPD) status, and demographic characteristics were also recorded.
Statistical analysis for baseline differences in categorical covariates between the three prophylaxis groups was performed using Chi-square testing. For tables with small expected cell counts, Fisher‚s exact test was employed instead. The comparability of the three prophylaxis groups in achieving balance over continuous covariates such as age and baseline CD4 count was assessed using the Kruskal-Wallis rank-sum test for one-way layouts. Kaplan-Meier curves were generated for time to MAC and survival differences between prophylaxis groups. Differences in survival were judged using the log rank and Gehan-Wilcoxon tests. Only P values < 0.05 were considered statistically significant.
Records of 338 HIV-seropositive patients with CD4 counts that remained <100¥106 cells/l during the study period were identified by the database and reviewed. A total of 146 patients was excluded because of failure to meet study criteria: 73 patients did not have surveillance cultures for dMAC during the study period (34 study clarithromycin prophylaxis, 26 no prophylaxis, 13 rifabutin), 19 patients had dMAC at baseline, 17 patients received clarithromycin in a total daily dose other than 500mg, 14 records were incomplete or missing, 13 patients participated in ACTG 196, five patients began MAC prophylaxis at or after the time of protease inhibitor therapy, four patients received azithromycin, and one patient was treated for tuberculosis during the study period.
Consequently, a total of 192 patients comprised the study population. Demographic characteristics and baseline laboratory values are presented in Table 1. In general, the three groups were very similar. Patients receiving clarithromycin had a lower CD4 count than those receiving either rifabutin or no prophylaxis (P=0.025). Patients in the no prophylaxis group were less likely to experience a CD4 count <50¥106 cells/l (P=0.002). Patients receiving clarithromycin were more likely to receive chronic fluconazole (P=0.002), although the clinical significance of this is not clear.
Duration of prophylaxis and follow up
The median duration of prophylaxis was 381 (range 35-1434) and 357 (range 37-1455) days for clarithromycin and rifabutin, respectively (P=0.43). The median follow-up was 770 (range 142-2,114), 682 (range 273-1843), and 454 (range 95-1399) days for the clarithromycin, rifabutin, and no prophylaxis groups, respectively (P<0.0001). The primary factor resulting in the median follow-up for the no prophylaxis group being shorter than either prophylaxis group was shorter survival. Table 2 summarizes the incidence of dMAC infection and the duration of prophylaxis in the present study and the results published for prospective studies of prevention of MAC infection [2,10,17,18].
Disseminated M. avium complex infection
A median of two surveillance cultures was obtained for clarithromycin and rifabutin subjects while a median of one surveillance culture was obtained for the no prophylaxis group during the observation. The mean number of surveillance cultures for the groups was: clarithromycin 2.27 (range 1-7), rifabutin 2.81 (range 1-10), and no prophylaxis 1.46 (range 1-5). Rifabutin patients had more surveillance cultures obtained because of the requirements of the expanded access program before it was licensed. Patients receiving no prophylaxis had fewer surveillance cultures obtained. More often, the reason cultures were obtained in patients on no prophylaxis was clinical suspicion of the diagnosis of dMAC or as part of the evaluation of fever.
The incidence of MAC bacteremia in patients assigned to the clarithromycin group was 9.5% (8/84) compared with 14.9% (7/47) in the rifabutin group and 34.4% (21/61) in the no prophylaxis group (P=<0.001 between all groups). The time to development of dMAC was longer for patients receiving either clarithromycin or rifabutin when compared with those receiving no prophylaxis (P<0.001, Figure 1). Among patients receiving clarithromycin, the estimated mean time to development of MAC was 1848 days compared with 930 days for the no prophylaxis group and 1581 days for the rifabutin group.
Susceptibility testing of MAC isolates began in December, 1992. Of the 36 isolates cultured during the study, 22 were tested for susceptibility to both clarithromycin and rifabutin (Table 3) by a broth dilution method. Resistance was defined as growth in the presence of concentrations of 4.0 and 1.0μg/ml for clarithromycin and rifabutin, respectively. Resistance was more likely to occur for the agent being given for prophylaxis.
Nine patients were lost to follow-up and were excluded from the survival analysis. A total of 119 (62.0%) patients died during the 6-year observation period; 54 (64.3%) deaths occurred among patients assigned to the clarithromycin group, 30 (65.2%) in the rifabutin control group, and 35 (60.3%) in the no prophylaxis control group. Kaplan-Meier analysis of the length of survival was increased for both prophylaxis groups when compared with the no prophylaxis group (P=0.004, Figure 2).
Survival once patients developed dMAC was similar to that in those who did not develop the infection (data not shown). All patients who developed dMAC were treated with a combination regimen containing clarithromycin.
The present study was undertaken to explore the efficacy of reduced dose clarithromycin as prophylaxis against dMAC infection in patients with advanced HIV infection. The use of reduced dose clarithromycin in this study was initiated at the same time as prospective studies with rifabutin and clarithromycin (at full dose) were also initiated and before the practice of prophylaxis of MAC infection became a standard of care.
The design of this study was observational and not prospective. The weaknesses of the study include lack of randomization to the three groups and lack of active assessment of adherence. Despite the lack of randomization, the study groups were similar in most baseline clinical characteristics. The lower baseline CD4 cell count of the clarithromycin group would create greater susceptibility to dMAC if clarithromycin was not active and could result in an underestimate of the effect of prophylaxis. The fact that not as many patients in the no prophylaxis group experienced a CD4 cell count <50¥106 cells/l could result in a bias against developing dMAC in this group. Yet despite these potential biases, once daily clarithromycin in an oral dose of 500mg was associated with a reduced incidence of dMAC infection in patients with advanced HIV disease when compared with no prophylaxis.
The incidence of dMAC infection in the advanced HIV disease population and the duration of prophylaxis of the present study are similar to published prospective studies of prevention of MAC infection [2,10,17,18]. The strength of the present study is its long follow-up period. The nearly 200 extra days of follow-up account for the high percentage of patients experiencing a CD4 count <50¥106 cells/l and an increased incidence of death.
In the present study, once daily clarithromycin was associated with a greater reduction in the incidence of dMAC than rifabutin, and in prolonged time to development of dMAC. In addition, both rifabutin and clarithromycin were associated with prolonged survival when compared with no prophylaxis and their effect upon survival was not significantly different from each other. This result is identical to prospective studies of azithromycin versus rifabutin or the combination and of full-dose clarithromycin versus high-dose rifabutin [7,19].
Clarithromycin is effective as treatment for dMAC infection at a dose of 500mg orally twice daily . The 1000mg oral twice daily dose was reported to be associated with higher mortality and is no longer recommended . The same 500mg oral twice daily dose was chosen to be studied in MAC prophylaxis trials. Therefore, the acute treatment dose is the currently recommended dose for prophylaxis. The minimum effective dose for prophylaxis is not known.
Clarithromycin is actively concentrated by phagocytes, with an intracellular concentration 9.2 times greater than the extracellular concentration . Liver and lung tissue concentrations also exceed plasma concentrations by 20 and 10 times, respectively . The serum half life of clarithromycin and its active metabolite are 3.1 and 6.9h, respectively .
Clarithromycin exhibits a post-antibiotic effect against MAC of 5.5 to 18h . Because of high intracellular concentrations, a long half life, and the presence of a post-antibiotic effect, once daily clarithromycin is very likely to be active against an intracellular pathogen such as MAC.
This study utilized a single daily dose of 500mg clarithromycin. Once daily dosing of clarithromycin provides a number of theoretical advantages: ease of administration, improved patient compliance, lower cost, and a reduced degree of drug interaction. The last is especially important in light of therapy with protease inhibitors, the steady-state concentration of which can be reduced by full-dose clarithromycin . The present study suggests that clarithromycin at a reduced once daily dose of 500mg may be an effective alternative prophylaxis regimen for dMAC infection.
The advent of highly active antiretroviral therapy (HAART) has greatly reduced the incidence of dMAC in AIDS patients [24,25]. The efficacy of once daily reduced-dose clarithromycin should ideally be evaluated by a randomized, prospective trial. However, the likelihood of successfully conducting such a trial in the near future is small since the CD4 cell count of most advanced AIDS patients rises and remains >100¥106 cells/l. For those patients whose CD4 cell count fails to rise or remains very low, chemoprophylaxis against dMAC remains an important clinical intervention.
The authors wish to thank Dr Timothy F. Murphy for scientific review and Marylouise Hewitt for editorial review of the manuscript and the patients and staff of Immunodeficiency Services at the Erie County Medical Center for their participation and support. The results presented here were presented in part at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, September 1997.
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