Original Article
A Controlled Trial of Aerosolized Pentamidine or Trimethoprim–Sulfamethoxazole as Primary Prophylaxis against Pneumocystis carinii Pneumonia in Patients with Human Immunodeficiency Virus Infection
N Engl J Med 1992; 327:1836-1841December 24, 1992
- Abstract
- Abstract
Background.
Primary prophylaxis against Pneumocystis carinii pneumonia (PCP) is recommended for patients with human immunodeficiency virus (HIV) infection if their CD4 cell counts are below 200 per cubic millimeter (0.2×109 per liter). Either aerosolized pentamidine or trimethoprim–sulfamethoxazole (co-trimoxazole) is commonly prescribed for prophylaxis, but the relative efficacy and toxicity of these agents are unknown.
Methods.
We conducted a multicenter trial involving 215 HIV-infected patients with no history of PCP but with CD4 cell counts below 200 per cubic millimeter. The patients were randomly assigned to one of three regimens: aerosolized pentamidine once a month, 480 mg of trimethoprim–sulfamethoxazole once a day (80 mg of trimethoprim and 400 mg of sulfamethoxazole), or 960 mg of trimethoprim–sulfamethoxazole once a day (160 mg and 800 mg, respectively). The cumulative incidence of PCP was estimated by Kaplan–Meier survival analysis.
Results.
After a mean follow-up of 264 days, 6 of the 71 patients in the pentamidine group had a confirmed first episode of PCP (11 percent), whereas none of the 142 patients in the two trimethoprim–sulfamethoxazole groups had PCP (P = 0.002). However, adverse events that required discontinuation of the medication were much more frequent in the trimethoprim–sulfamethoxazole groups (17 and 18 patients) than in the pentamidine group (2 patients). The adverse reactions occurred significantly sooner in the group given 960 mg of trimethoprim–sulfamethoxazole than in the group given 480 mg (mean time, 16 vs. 57 days; P = 0.02).
Conclusions.
For patients with HIV infection, trimethoprim–sulfamethoxazole taken once a day is more effective as primary prophylaxis against PCP than aerosolized pentamidine administered once a month, although adverse drug reactions are more frequent with trimethoprim–sulfamethoxazole. (N Engl J Med 1992;327:1836–41.)
Media in This Article
Figure 1
Probability of Survival without PCP, as a Function of Time in the Trial.Figure 2
Probability of Survival without Adverse Events, as a Function of Time in the Trial.Article Activity
- Article
PNEUMOCYSTIS CARINII pneumonia (PCP) is the most common serious opportunistic infection among patients with human immunodeficiency virus (HIV) infection, occurring at some point in at least 85 percent of patients.1 2 3 The case fatality rate ranges from 5 to 40 percent and is highest among patients with acute respiratory failure.2 3 4 5 6 Masur et al.7 and other authors3 , 8 , 9 found in retrospective studies that HIV-infected patients with peripheral-blood CD4 lymphocyte concentrations of more than 350 per cubic millimeter (0.35×109 per liter) did not have PCP, whereas the incidence increased as the CD4 cell count declined below 200 per cubic millimeter (0.2×109 per liter). The prospective Multicenter AIDS Cohort Study has confirmed these data.8 , 10 Early primary prophylaxis reduces morbidity and mortality by preventing first episodes of PCP, and its effect is independent of the effect of zidovudine.10 These data formed the basis of the recommendation of the Centers for Disease Control and Prevention that patients with HIV infection and CD4 cell counts lower than 200 per cubic millimeter should receive primary prophylaxis against PCP.1 , 11
Several drugs have proved effective in both primary and secondary prophylaxis against PCP. Of these, aerosolized pentamidine and trimethoprim–sulfamethoxazole (co-trimoxazole) are used most often. Aerosolized pentamidine has been used in different dosages for both primary12 13 14 and secondary12 , 14 15 16 17 prophylaxis. A dose of 300 mg of aerosolized pentamidine every four weeks seems to be best, although episodes of PCP have been described in patients receiving this type of prophylaxis.12 , 13 , 18 The incidence of PCP per year of observation was 8.6 percent in a placebo-controlled trial of primary prophylaxis with pentamidine.13 Approximately the same rate of relapse was found in trials of secondary prophylaxis.14 15 16 17 Since aerosolized pentamidine is hardly absorbed, systemic toxicity is rare. However, because of its lack of systemic effects, several cases of extrapulmonary pneumocystosis have occurred.19 20 21
Trimethoprim–sulfamethoxazole at a dose of 960 mg given twice daily with folinic acid (5 mg once daily) has been found highly effective in a study of primary prophylaxis in patients at high risk. However, adverse effects developed in half the patients, and the drug had to be discontinued in 17 percent, mainly because of generalized erythroderma and fever.22 , 23 When used in conjunction with zidovudine, trimethoprim–sulfamethoxazole can aggravate anemia and neutropenia, but the risk of this complication does not appear to be high.24 , 25 The prescription of one tablet of trimethoprim–sulfamethoxazole (960 mg once a day) for secondary prophylaxis became common practice in the Netherlands in early 1988, on the basis of clinical evidence that a lower dose reduced adverse reactions to the drug but maintained its efficacy. Several studies supported this supposition, although most of them were retrospective and hence difficult to interpret.17 , 23 , 26 27 28 Moreover, the study of Hughes et al. involved patients without HIV infection.26
No studies have yet been reported in which aerosolized pentamidine has been compared with trimethoprim–sulfamethoxazole in low doses as agents for primary prophylaxis against PCP in persons with HIV infection. We therefore conducted a prospective, randomized multicenter study to compare the efficacy and toxicity of aerosolized pentamidine (300 mg every four weeks) with the efficacy and toxicity of trimethoprim–sulfamethoxazole (960 or 480 mg once a day) in HIV-infected patients with CD4 cell counts below 200 per cubic millimeter.
Methods
Patients
Patients were recruited from the outpatient clinics of 12 Dutch hospitals and 1 Danish hospital, beginning February 1, 1990. The protocol and consent forms were approved by the investigational review board of each participating hospital. Patients were included in the study if they were seropositive for HIV as determined by enzyme-linked immunosorbent assay and Western blotting, had a peripheral-blood CD4 lymphocyte concentration below 200 per cubic millimeter, had a Karnofsky index of at least 60, and were 16 years old or older. Patients were excluded if they had previously had an episode of PCP, had been treated with trimethoprim–sulfamethoxazole or pentamidine within two months of entering the study, were known to be intolerant of trimethoprim–sulfamethoxazole or pentamidine, had a neutrophil count below 1000 per cubic millimeter (1.0×109 per liter), had a platelet count below 50,000 per cubic millimeter (50×109 per liter), had a serum alanine or aspartate aminotransferase level more than three times the upper limit of normal for the hospital, or had a serum creatinine level above 4.5 mg per deciliter (400 μmol per liter).
Study Design
After the patients had given their informed consent, they were assigned to one of the three following treatment regimens by central randomization: 300 mg of aerosolized pentamidine isethionate given every four weeks, 480 mg of trimethoprim–sulfamethoxazole (80 mg of trimethoprim and 400 mg of sulfamethoxazole) given once a day, or 960 mg of trimethoprim–sulfamethoxazole (160 mg and 800 mg, respectively) given once a day. Treatment was not blinded. Pentamidine was dissolved in 6 ml of distilled water and was aerosolized over a period of 35 to 40 minutes with a Respirgard II nebulizer linked to a compressed-air source with an airflow of 6 liters per minute. The patient remained upright during the procedure. To prevent bronchospasm, 5 mg of albuterol (salbutamol) in a 2-ml solution was aerosolized for 15 minutes before pentamidine was administered. Each treatment was supervised by an experienced nurse.
Evaluation and Follow-up
At entry, a study physician (who was also the patient's primary care physician) took each patient's history and performed a physical examination, blood tests (including complete blood counts, liver-function tests, serum creatinine measurement, and a CD4 cell count), chest radiography, and a carbon monoxide—diffusion test. At least every four weeks, the patient was interviewed and any new symptoms or adverse events were noted. All blood tests were repeated monthly except the CD4 cell count, which was performed every three months. Each physician had been advised that therapy might be interrupted for 7 to 10 days to assess the effect of drug withdrawal on severe reactions. The use of antihistaminic agents was allowed. If the physician considered withdrawing the patient from the study, he or she was advised to contact one of the study coordinators to review the data in order to standardize the interview with the patient and reach a final decision. Whenever symptoms or signs of lower respiratory tract infection developed, the patient underwent chest radiography, determination of the carbon monoxide—diffusion capacity or gallium scanning (or both), and arterial blood gas measurement. When the results of these examinations were abnormal, an induced sputum specimen was obtained or bronchoalveolar lavage was performed.
All patients, including those who could not tolerate either drug, were followed for at least one year unless they withdrew, were noncompliant, or died. The study end point was the demonstration of P. carinii microorganisms in induced sputum, bronchoalveolar-lavage fluid, a specimen from a transbronchial (or open) biopsy, or histologic or cytologic material obtained from extrapulmonary sites during life or after death.
Statistical Analysis
The 215 patients who took part in the study were evaluated on an intention-to-treat basis. All end points were included in the analysis, whether or not patients were taking the initial study drug when the end point occurred.
The cumulative incidence of PCP was estimated by Kaplan–Meier survival analysis29 with the EGRET Statistical Package.30 The cumulative incidence of adverse events was computed in a similar way. In the survival analysis, adverse events were considered to indicate treatment failure. PCP was considered as a censored observation among all other censored observations. The Mantel log-rank test was used to test the equality of life tables. The Wilcoxon two-sample test was used for unpaired comparisons. The significance of the differences in nominal-scale data was determined by chi-square analysis and Fisher's exact test, with use of the SAS computer program.31 A P value of 0.05 or less was considered to indicate statistical significance.
Results
A total of 215 patients were enrolled from February 1, 1990, to October 10, 1991 (170 patients in the Netherlands and 45 in Denmark). Seventy-two patients were assigned to pentamidine treatment, 72 to treatment with 480 mg of trimethoprim–sulfamethoxazole, and 71 to treatment with 960 mg of trimethoprim–sulfamethoxazole. At the time of evaluation, 91 patients had been studied for at least one year. The mean period of observation was 264 days in the group given pentamidine, 288 days in the group given 480 mg of trimethoprim–sulfamethoxazole, and 277 days in the group given 960 mg of trimethoprim–sulfamethoxazole.
Two patients, one assigned to treatment with 480 mg of trimethoprim–sulfamethoxazole and the other to pentamidine, were disqualified after they entered the study because they did not meet the criteria for inclusion. Their chest films and carbon monoxide—diffusion values were abnormal because of preexisting PCP. Data on these patients were therefore excluded from all analyses. Seventeen patients dropped out of the study because they missed two consecutive appointments, did not take the medication regularly, or wanted to withdraw (six patients assigned to pentamidine treatment, six assigned to treatment with 480 mg of trimethoprim–sulfamethoxazole, and five assigned to treatment with 960 mg of trimethoprim–sulfamethoxazole).
The three treatment groups were balanced with respect to age, sex, risk factors for HIV, disease stage (as defined by the Centers for Disease Control and Prevention32), and CD4 cell count (Table 1Table 1
Base-Line Characteristics of the Study Groups.). At the start of the study, significantly more patients in the pentamidine group used zidovudine than in either trimethoprim–sulfamethoxazole group (65 percent vs. 55 percent [480 mg of trimethoprim–sulfamethoxazole] and 44 percent [960 mg]; P = 0.04). Among the concomitant medications other than zidovudine, systemic antifungal agents were used most frequently. At entry and during the study, the patients in the pentamidine group used more antifungal agents than the patients in either trimethoprim–sulfamethoxazole group (at the start of the study, 18 patients vs. 11 patients [480 mg] and 12 patients [960 mg]; during the study, 9 vs. 3 and 3, respectively); however, the differences between the treatment groups were not significant (P = 0.08). The rate of use of other medications, such as antiviral agents (other than antiretroviral agents), cytostatic agents, or antimicrobial agents, was low, and there were also no significant differences between the groups.Figure 1Figure 1
Probability of Survival without PCP, as a Function of Time in the Trial. shows the results of the evaluation in October 1991. PCP occurred in six patients in the pentamidine group. P. carinii microorganisms were found in bronchoalveolar-lavage fluid from five of these patients and in induced sputum from one patient; PCP was diagnosed after 41, 71, 93, 151, 268, and 458 days of treatment. The cumulative incidence of PCP in the pentamidine group was 11 percent per year (95 percent confidence interval, 4 to 23 percent). Three of the six patients took zidovudine. In contrast, no cases of PCP occurred in either trimethoprim–sulfamethoxazole group. Thus, the actual efficacy of pentamidine was 89 percent, as compared with 100 percent for trimethoprim–sulfamethoxazole in both groups. Comparison of the cumulative incidence and actual efficacy by means of the Mantel log-rank test showed that there was a significant difference between the trimethoprim–sulfamethoxazole groups, and between these groups combined and the pentamidine group (P = 0.002). Comparison of the patients who had PCP with all the other patients did not reveal any significant differences in their characteristics at entry, such as their CD4 cell count, disease stage, or zidovudine use.Seventy-two patients discontinued taking their study drug for reasons other than PCP (Table 2Table 2
Reasons for Discontinuation of Trial Medication by Patients.). Eighteen patients died — eight patients taking pentamidine and five each in the two trimethoprim–sulfamethoxazole groups. Three patients died of toxoplasma encephalitis in the pentamidine group, whereas none died of this cause in either trimethoprim–sulfamethoxazole group (P = 0.03). One patient in the pentamidine group died of HIV encephalopathy, and four of HIV wasting syndrome. One patient in the group given 480 mg of trimethoprim–sulfamethoxazole died of disseminated cytomegalovirus infection, one of HIV encephalopathy, one of cryptococcal meningitis, and two of HIV wasting syndrome. The five patients in the group given 960 mg of trimethoprim–sulfamethoxazole died of one of the following causes each: disseminated cryptococcosis, nonHodgkin's lymphoma, HIV encephalopathy, HIV wasting syndrome, and suicide. Although few autopsies were done, clinical observation indicated that these deaths were due to illnesses other than PCP.Thirty-seven patients had to stop taking their medication because they could not tolerate it. Two patients in the pentamidine group stopped after 313 and 456 days because of cough and bronchospasm despite the administration of albuterol. Seventeen of the patients taking 480 mg of trimethoprim–sulfamethoxazole and 18 of those taking the 960-mg dose had adverse reactions necessitating discontinuation of the drug. The adverse events were not life-threatening and consisted of fever (temperature >39°C), generalized exanthem, nausea, and vomiting. No patient had severe neutropenia (<500 neutrophils per cubic millimeter [0.5×109 per liter]). The cumulative incidence of adverse events after three months was zero in the pentamidine group, 21 percent (95 percent confidence interval, 12 to 32 percent) in the group given 480 mg of trimethoprim–sulfamethoxazole, and 26 percent (95 percent confidence interval, 17 to 38 percent) in the group given 960 mg (P<0.001). The mean number of days to the onset of adverse reactions in the patients treated with 480 mg of trimethoprim–sulfamethoxazole was 57 (range, 7 to 191), as compared with 16 days (range, 5 to 35) in those treated with 960 mg (P = 0.02) (Fig. 2Figure 2
Probability of Survival without Adverse Events, as a Function of Time in the Trial. and Table 3Table 3
Adverse Reactions Requiring Discontinuation of the Study Drug.). There were no differences between the two trimethoprim–sulfamethoxazole groups in the types of adverse effects (Table 3). Neither PCP nor death occurred in the 37 patients who discontinued their initial drug because of side effects. Treatment was changed from trimethoprim–sulfamethoxazole to pentamidine in 31 of the 35 patients with adverse drug effects. The mean length of the follow-up of these 31 patients after the switch in medication was 362 days (range, 10 to 596). The remaining 4 of these 35 patients and the 2 patients who could not tolerate pentamidine did not take a prophylactic agent after they had stopped taking their initial drug (mean length of follow-up, 160 days; range, 0 to 475).Discussion
This prospective study compared two doses of oral trimethoprim–sulfamethoxazole with aerosolized pentamidine as primary prophylaxis against PCP in HIV—infected patients with a CD4 cell count below 200 per cubic millimeter. Interim analysis clearly showed that primary prophylaxis against PCP with oral trimethoprim–sulfamethoxazole was more effective than that with aerosolized pentamidine. The cumulative incidence of PCP among the patients treated with trimethoprim–sulfamethoxazole was zero, whereas it was 11 percent among the pentamidine-treated patients (P = 0.002). The investigators of the Dutch AIDS Treatment Group, together with Danish colleagues and the Dutch AIDS Patients Association, therefore decided to stop the study.
To support our finding that pentamidine was less effective than trimethoprim–sulfamethoxazole as primary prophylaxis against PCP, we analyzed several factors that may have influenced the effect of pentamidine in a negative way. First, the interval between the initiation of pentamidine therapy and the diagnosis of PCP ranged from 41 to 458 days. Evaluation of the patients' records indicated that none had missed taking their doses of pentamidine. Thus, inadequate dosing or noncompliance could not have influenced outcome. Second, the pentamidine-treated patients did not differ from the patients treated with trimethoprim–sulfamethoxazole with respect to variables such as risk factors for HIV infection, the stage of HIV infection, and the CD4 cell count. The trimethoprim–sulfamethoxazole groups and the pentamidine group did differ in the percentage of patients taking zidovudine (55 percent [480 mg] and 44 percent [960 mg] vs. 65 percent). However, as other investigators have shown,10 it is unlikely that zidovudine interferes with the effect of aerosolized pentamidine in preventing PCP. Finally, it has been suggested that the upper lung lobes are especially prone to infection if the patient inhales pentamidine while upright.33 , 34 However, none of our patients had PCP in the upper lobes, indicating that the lack of efficacy of pentamidine was probably not related to their position while they were inhaling it.
Since trimethoprim–sulfamethoxazole, unlike pentamidine, may protect against other infections, such as those due to salmonella, shigella, and nocardia species and Haemophilus influenzae, Streptococcus pneumoniae, Isospora belli, Listeria monocytogenes, and Toxoplasma gondii, we analyzed the occurrence of opportunistic infections other than PCP. Toxoplasmic encephalitis was diagnosed in three patients in the pentamidine group. This observation agrees with the results of other studies, which suggest that trimethoprim–sulfamethoxazole has a protective effect against toxoplasmic encephalitis23 , 28 , 35
PCP was not diagnosed during follow-up in the 37 patients who stopped taking their initial drug because of adverse effects. It appears that the absence of PCP in these patients cannot be explained by the use of concomitant medication.
Our study clearly shows that trimethoprim–sulfamethoxazole has greater efficacy than pentamidine as prophylaxis against PCP, but it also has a higher incidence of adverse effects. Interestingly, the incidence and types of adverse reactions were similar in both trimethoprim–sulfamethoxazole groups, but the side effects occurred significantly sooner in the group given the higher dose (960 mg vs. 480 mg, 16 vs. 57 days; P = 0.02). These adverse effects may be a result of dose-related cumulative toxicity, caused by the accumulation of reactive metabolites of sulfamethoxazole, rather than of hypersensitivity.36 Because HIV-infected patients have a systemic glutathione deficiency, their capacity to scavenge these reactive metabolites is reduced, thus increasing their exposure to these potential toxins.37
We conclude that the greater efficacy of oral trimethoprim–sulfamethoxazole as compared with aerosolized pentamidine makes trimethoprim–sulfamethoxazole the drug of choice for primary prophylaxis against PCP in spite of the higher incidence of adverse events among patients given trimethoprim–sulfamethoxazole. Although our study was not designed to compare the efficacy of the 480-mg dose of trimethoprim–sulfamethoxazole with that of the 960-mg dose, our results show that these doses have equal efficacy. Other factors, such as cost and convenience of use, also favor trimethoprim–sulfamethoxazole. Data from the United States and Europe show that the cost of trimethoprim–sulfamethoxazole (in a dose of 960 mg twice daily) is less than a fourth of the cost of aerosolized pentamidine, assuming these agents have the same efficacy.38 , 39
Supported by a grant (90–145) from the Dutch Ministry of Public Health and a grant from Rhône-Poulenc Pharma, the Netherlands.
*Other members of the Dutch AIDS Treatment Group who participated in this study are listed in the Appendix.
We are indebted to S.A. Danner for assistance in initiating the study, to S.A. Danner and L. Kater for their critical reading of the manuscript, and to medical students E. Jansen and C.E. van Iperen for their assistance in collecting the data.
Source Information
From the Department of Internal Medicine, Section of Immunology and Infectious Diseases, University Hospital Utrecht, Utrecht (M.M.E.S., A.I.M.H., J.C.C.B.); the Department of Clinical Microbiology and Laboratory for Infectious Diseases, University Hospital Utrecht, Utrecht (A.I.M.H.); the Department of Epidemiology, Utrecht University, Utrecht (Y.G.); the Department of Internal Medicine, AIDS Unit, Academic Medical Center, Amsterdam (J.K.M.E.S.); Onze Lieve Vrouwe Gasthuis, Amsterdam (J.P.H.J.F.); University Hospital, Rotterdam (I.M.E.E.); and U-Gene Research, Utrecht (A.F.P.K.) — all in the Netherlands; and the Department of Infectious Diseases, Kobenhavns Kommunes, Hvidovre Hospital, Hvidovre, Denmark (T.L.N.). Address reprint requests to Dr. Schneider at the University Hospital Utrecht, F02.126, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
Appendix
The following investigators from the Dutch AIDS Treatment Group participated in this study: S.A. Danner (Academic Medical Center, Amsterdam), H.M. Weigel (Onze Lieve Vrouwe Gasthuis, Amsterdam), H.G. Sprenger (University Hospital, Groningen), R.H. Kauffmann (Leyenburg Hospital, The Hague), J.W. van 't Wout (University Hospital, Leiden), P.L. Meenhorst (Slotervaart Hospital, Amsterdam), C.H.H. ten Napel (Medisch Spectrum Twente, Enschede), G. Schreij (University Hospital, Maastricht), R.W. ten Kate (Elisabeth's Gasthuis, Haarlem), J.R. Juttmann (Elisabeth Hospital, Tilburg), P.P. Koopmans (University Hospital, Nijmegen), and S. Nielssing (Hvidovre Hospital, Kobenhavns, Denmark).
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