Efficacy and tolerance of intermittent versus daily cotrimoxazole for PCP prophylaxis in HIV-positive patients

BRIEF CLINICAL

carinii pneumonia (PCP) was the most common presenting manifestation of the acquired immunodeficiency syndrome (AIDS), and 85% of AIDS patients developed PCP at some point during Kansas City, Missouri their illness [1,2]. Several recent 1. Bonner JR, Alexander WJ. Dismukes WE, et al. studies have shown that prophyDisseminated histoplasmosis in patients with the lactic administration of aerosolacquired immune deficiency syndrome. Arch Intern ized pentamidine or cotrimoxaMed 1984; 144: 2178-81. 2. Wheat LJ, Slama TG, Zeckel ML. Histoplasmosis zole (trimethoprim-sulfamethoxin the acquired immunodeficiency syndrome. Am J azole) is effective in preventing Med 1985; 78: 203-10. PCP [3,4]. However, neither drug 3. Johnson PL, Khardori N, Najjar AF, Butt F, Mansell PW. Sarosi GA. Progressive disseminated histois ideal: atypical PCP or systemic plasmosis in patients with acquired immunodefiinfection can develop in patients ciency syndrome. Am J Med 1988; 85: 152-8. receiving aerosolized pentami4. Kurtin PJ, McKinsey DS, Gupta MR, Driks MR. dine, and dermatologic and heHistoplasmosis in patients with acquired immunodeficiency syndrome: hematologic and bone marmatologic adverse effects occur in row manifestations. Am J Clin Pathol 1990; 93: up to 50% of AIDS patients tak367-72. ing cotrimoxazole [P71. It would 5. Driks MR, Gupta MR, McKinsey DS. Neihart RE, be helpful to define a cotrimoxaO’Connor MC. Gastrointestinal histoplasmosis in patients with acquired immunodeficiency synzole regimen that has the same drome. In: Program and abstracts of the 30th Inefficacy with less toxicity. Beterscience Conference on Antimicrobial Agents and cause thrice-weekly cotrimoxaChemotherapy. American Society for Microbiology, zole is effective when adminis1990: 298. 6. Graham BD, McKinsey DS. Driks MR, Smith DL. tered to leukemic children for Colonic histoplasmosis in acquired immunodeficienPCP prophylaxis [8], many phycy syndrome. Dis Colon Rectum 1991; 34: 185-90. sicians in our group began pre7. McKinsey DS. Gupta MR, Riddler SA, Driks MR, scribing this regimen for AIDS Smith DL, Kurtin PJ. Long-term amphotericin B therapy for disseminated histoplasmosis in patients patients. We retrospectively rewith the acquired immunodeficiency syndrome. viewed medical records to deterAnn Intern Med 1989; 111: 655-9. mine if the decreased dosing fre8. Graybill JR. Histoplasmosis and AIDS. J Infect Dis quency maintained efficacy and 1988; 623: 26. 9. Wheat LJ, Connolly-Stringfield PA, Baker RL, et reduced adverse reactions. al. Disseminated histoplasmosis in the acquired imPatients and Methods. Medimunodeficiency syndrome: clinical findings, diagnocal records from our HIV (human sis and treatment, and review of the literature. Medicine (Baltimore) 1990; 69: 361-74. immunodeficiency virus) care 10. Nightingale SD, Parks JM, Pounders SM, Burns practices were reviewed retroDK, Reynolds J. Hernandez JA. Disseminated histospectively if patients had taken plasmosis in patients with AIDS. South Med J 1990; cotrimoxazole and met the fol83: 624-30. lowing criteria for PCP prophySubmitted April 10, 1991, and accepted in revised laxis: (1) CD4 cell count less than form June 24, 1991 200/mm3, (2) CD4 cells less than (NOTE: This work was supported in part by Grant 20% of total lymphocytes, or (3) 600021-g-CT from the American Foundation for AIDS Research.) prior episode(s) of PCP. Patients were all members of the Penn Affiliates Clinical Consortium HIVpositive cohort and had given inEFFICACYAND TOLERANCEOF formed consent for the review. INTERMITTENT VERSUSDAILY Double-strength cotrimoxazole COTRIMOXAZOLEFOR PCP tablets (160 mg trimethoPROPHYLAXISIN HIV-POSITIVE prim/800 mg sulfamethoxazole) PATIENTS were administered orally one or two times daily either MonPrior to the development of che- day/Wednesday/Friday or 7 days a week in a nonrandom manner moprophylaxis, Pneumocystis DAVID S. MCKINSEY, M.D. MALA R. GUPTA, M.D. MICHAEL R. DRIKS, M.D. DAVID L. SMITH, M.D. MAR Y O’CONNOR, M.D. Kansas City AIDS Research Consortium

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1992

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OBSERVATIONS

based on physician preference. Most patients received concomitant zidovudine, at doses between 500 and 1,200 mg/day. Medical records were reviewed for evidence of PCP and for possible adverse effects. The diagnosis of PCP was considered “presumed” if made on the basis of radiologic and clinical findings without microbiologic confirmation, or “definite” if the organisms were visualized in sputum or in bronchial washings. Criteria for hematologic complications (set retrospectively) were as follows: leukopenia-decrease of white blood cell count to less than or equal to 2,000/mm3; anemia-decrease in hemoglobin level of greater than or equal to 2 g from baseline or to less than or equal to 6.5 mg/dL. Diagnosis by the patient’s physician of dermatologic or gastrointestinal toxicity was accepted at face value. Treatment failure was defined as development of either PCP or any potential adverse event that caused the physician to discontinue the drug. Incidence density ratios (IDRs) with exact unadjusted 95% confidence intervals (CIs) and exact p values were computed to compare the group receiving prophylaxis daily with the group on the thrice-weekly regimen with and without controlling for zidovudine dose [9]. Descriptive statistics (including chisquare tests) were obtained using the computer program SAS. Results. Ninety-nine patients who had received cotrimoxazole for prophylaxis were available for review; 62 received daily dosing and 37 received the drug thrice weekly. In the every-day group, two thirds of patients received the drug once daily and one third twice daily. In the thrice-weekly group, equal numbers received once- or twice-daily dosing. Ninety-five percent of the study population were men, 55% were white, Journal

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BRIEF CLINICAL

OBSERVATIONS

TABLE I Adverse

Effects No. (%)

Months at Risk

Incidence

p Value

All adverse effects Daily 3xlweek

34 (66) 15 (40.5)

328.5 237.6

0.104 0.063

0.11

Rash Daily 3xlweek

17 (27.4) 3 (8.1)

328.5 237.6

0.052 0.013

0.01

Y i:4ip

328.5 237.6

0.027 0.004

0.04

Daily 3xlweek

6 (9.71 4 (10.8)

328.5 237.6

0.018 0.017

0.92

Leukopenia Daily 3xiweek

ZFiP

328.5 237.6

0.027 0.013

0.25

Nausea/vomiting Daily 3 x/week

and 70% were homosexual. The demographics, zidovudine dose, and proportion of patients receiving primary or secondary prophylaxis were similar in both groups except that the daily group ,contained more whites (p = 0.0001) and more homosexuals (p = 0.02). Only one patient, known to be inconsistently compliant with all medications, developed PCP in 566 months at risk, a rate of 0.02 per year. The incidence of adverse effects requiring discontinuation of cotrimoxazole was analyzed by patient-months at risk and adjusted for zidovudine dose. The daily group was 2.4 times more likely to experience adverse reactions than the thrice-weekly group (IDR = 2.4; CI, 1.29 to 4.55; P = 0.005). The most common cause for termination of the drug in the daily group was rash, occurring in 27% of patients. The daily group was four times more likely to develop rash (IDR = 4.1; CI, 1.31 to 17.5; p = 0.01) and six times more. likely to experience nausea and vomiting (IDR = 6.5; CI, 1.07 to 143.9; p = 0.04) than the intermittent dosing group. Anemia was the most common reason cited for discontinuation in the thrice-weekly group, oc228

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curring in 11% of patients (Table 1). Comments. HIV-infected patients with CD4 cell counts below 200/mm3 have a 24% incidence of PCP over the next 12 months [Z]. After the first episode of PCP, the frequency of PCP increases to 60% over 12 months if prophylactic measures are not taken [2]. In 1984, Fischl et aE [4] demonstrated the efficacy of daily cotrimoxazole for PCP prophylaxis in the AIDS population, and in 1987, Hughes and colleagues [8] showed that intermittent cotrimoxazole prophylaxis was efficacious in immunocompromised patients without AIDS. On the basis of these studies, clinicians in our practices began empirically prescribing intermittent cotrimoxazole (Monday/Wednesday/ Friday) for PCP prophylaxis. Because of differing prescribing preferences among our clinicians, we were able to compare efficacy and tolerance retrospectively for daily versus thrice-weekly treatment. We found intermittent cotrimoxazole .equally efficacious as daily administration: no cases of PCP occurred in 237.6 patientmonths in the intermittent group versus one case of PCP in 328.5 of Medicine

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patient-months in the daily group. Seventy-three percent of our study patients were receiving primary prophylaxis, a population with a,24% incidence of PCP per year [2]. ‘Our other 27% of patients had already had one episode of PCP; a predicted recurrence rate of 60% has been described without prophylaxis in this group [2]. On the basis of these considerations and the number of months at risk for our study group, we would have expected nine cases of PCP in our daily group and eight cases in our intermittent group had they not received prophylaxis. This efficacy rate compares favorably with that for aerosolized pentamidine prophylaxis, in which the failure rate is 8% to 15% [5,6]. Clinical events leading to discontinuation of therapy occurred in approximately 50% of the entire study group; when analyzed by patient-months at risk and holding the zidovudine dose constant, significantly more events occurred in the daily treatment group. Anemia and leukopenia were common, but almost all episodes occurred in patients receiving high-dose zidovudine (greater than 1,000 mg/day). It is certainly plausible that many patients had cotrimoxazole discontinued primarily due to zidovudine marrow suppression. The greater incidence of rash in the daily dosage group may seem surprising because one might expect drug sensitization to occur more often with an intermittent dosing schedule.. The possibility of a dose-related effect is interesting and should be studied further. Several limitations of our retrospective review should be considered. First, although virtually no patients developed PCP, it could be argued that there were relatively few patient-months at risk. However, several other groups have recently reported similar success with intermittent

BRIEF CLINICAL

regimens [lo-121. Our study is unique in providing comparative efficacy and tolerance data for intermittent and daily dosing. Second, both once- and twicedaily administration of cotrimoxazole was used and may have confounded the assessment of adverse effects. Finally, because half of our patients’ months on study occurred during a period when the standard dose of zidovudine was 1,200 mg/day, the incidence of marrow-related toxicity is probably high compared with current treatment standards. Despite these limitations, our experience, which showed no episodes of PCP in 237.6 patient-months of prophylaxis administered intermittently, argues that the thrice-weekly regimen can be used with efficacy equal to that of a daily regimen, with less frequent dosing, lower

cost, and decreased dose-related toxicity. ROB ROY MA®OR,M.D. AMYS. MoRGAN,P~~~~.D. AMYL. GRAZIANI, Pharm.D. NANCYA. PIETROSKI,Pharm.D. IANFRANK,M.D. MICHAELN.BRAFFMAN,M.D. JOHNJ. STERN,M.D. R.MICHAELBUCKLEY,M.D. University of Pennsylvania Philadelphia, Pennsylvania 1. Centers for Disease Control. AIDS Weekly Surveillance Report, January 30, 1989: l-5. 2. Centers for Disease Control. Guidelines for prophylaxis against Pneumocysfis cariniipneumonia for persons infected with human immunodeficiency virus, MMWR 1989; 38 (S-5): l-9. 3. Leoung GS, Feigal DW, Montgomery AB, et al. Aerosolized pentamidine for prophylaxis against Pneumocystis carinii pneumonia. N Engi J Med 1990; 323: 769-75. 4. Fischl MA, Dickinson GM, LaVoie L. Safety and efficacy of sulfamethoxazole and trimethoprim chemoprophylaxis for Pneumocysfis cariniipneumonia in AIDS. JAMA 1988; 259: 1185-9. 5. Abd AG, Nierman DM, llowite JS, Pierson RN, Bell ALL. Bilateral upper lobe Pneumocystis cariniipneumonia in a patient receiving inhaled pentamidine prophylaxis. Chest 1988; 94: 329-31.

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OBSERVATIONS

6.Scannell KA. Atypical presentation of Pneumo cystis carinii pneumonia in a patient receiving inhalational pentamidine. Am J Med 1988; 85: 881-4. 7. Gordin FM, Simon GL, Wofsy CB, Mills J. Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1984; 100: 495-9. 8. Hughes WT, Rivera GK, Schell MJ, Thornton D, Lott L. Successful intermittent chemoprophylaxis for Pneumocystis cariniipneumonitis. N Engl J Med 1987: 316: 1627-32. 9. Guess HA, Lydick EG. Small RD, eta/. Exact binomial confidence intervals for the relative risk in follow-up studies with sparsely stratified incidence density data. Am J Epidemiol 1987; 125: 2. 10. Raviglione MC, Nsah EN, Cortes H, et a/. Intermittent co-trimoxazole prophylaxis against Pneumocysfiscarifliipneumonia. Lancet 1990; 336: 180. 11. Ruskin .I, LaRiviere M. Low-dose co-trimoxazole for prevention of Pneumocysfis cariniipneumonia in human immunodeficiency virus disease. Lancet 1991; 337: 468-71. 12. Wormser GP, Horowitz HW, Duncanson FP, et al. Low-dose intermittent trimethoprim-sulfamethoxazole for prevention of Pneumocysfis carinii pneumonia in patients with human immunodeficiency virus infection. Arch Intern Med 1991; 151: 688-92. Submitted

Journal

March 29,1991,

of Medicine

and accepted in revised form June 24, 1991

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