Guidelines for Prophylaxis Against Pneumocystis carinii Pneumonia for Persons Infected with Human Immunodeficiency Virus

Pneumocystis carinii pneumonia (PCP), the most common presenting manifestation of the acquired immunodeficiency syndrome (AIDS), is a major and recurring cause of morbidity and mortality for persons infected with the human immunodeficiency virus (HIV). In recent years, important advances have been made in understanding which patient subpopulations are athighest risk for developing PCP and in the design of chemotherapeutic regimens that can reduce the frequency of this illness. Recently, a number of experts* convened by the National Institutes of Health independently reviewed data on prophylaxis against PCP among persons infected with HIV, and then provided recommendations to the U.S. Public Health Service concerning which persons should receive prophylaxis and what specific prophylactic regimens should be used. The resulting guidelines are detailed below. BACKGROUND

Since the early 1980's, management of PCP has become increasingly successful, and several effective chemotherapeutic regimens are available (1). However, such conventional therapy as trimethoprim-sulfamethoxazole or parenteral pentamidine is often complicated by adverse reactions that may require termination of the therapy (2), and the mortality for first episodes of PCP is still 5%-20%. Thus, prevention of PCP is a preferred alternative to treating patients for successive episodes of this disease.

Prophylaxis against PCP is categorized as primary if the goal is to prevent an initial episode for a person who has never had PCP. Prophylaxis is categorized as secondary if the goal is to prevent subsequent episodes for a person who has already had at least one episode of PCP. Risk of an Initial Episode of PCP

Immunologic and clinical parameters can be helpful in determining which HIV-infected persons are at particular risk for having PCP and, therefore, which are most likely to benefit from prophylaxis against PCP. In the Multicenter AIDS Cohort Study (MACS), an ongoing prospective epidemiologic investigation of the transmission and natural history of HIV infection among homosexual men (3), there was a strong association (p less than 0.001) between the baseline numbers of T-helper lymphocytes (CD4+ cells) and the incidence of PCP (Table 1). Additionally, a Kaplan-Meier estimate for 323 participants whose counts of CD4+ cells were less than 200/mm3 during the study showed that the proportions who had PCP by 6, 12, and 36 months were 13%, 24%, and 39%, respectively.

Similar results were seen when MACS data were analyzed by fraction of CD4+ cells expressed as a percentage of total lymphocytes rather than by absolute number of such cells. In a multivariate analysis of the prospective MACS data, thrush and persistent fever (temperature of greater than 100 degrees F) were additional independent predictors of the development of PCP among patients with CD4+ counts of less than 200/mm3at their most recent evaluation (Panel of experts,* Phair and Munoz). A retrospective study to investigate the levels of CD4+ at which adult patients develop PCP confirms the MACS data (4). For the 49 episodes of PCP studied, the CD4+ counts were 1-365/mm3 (median 26/mm3), and the percentage of circulating lymphocytes that were CD4+ positive was 0-25% (median 4%) within 60 days before the episode (Figure 1). Risk of Recurrent PCP

For HIV-infected persons who have had one episode of PCP, there is a high probability that a second episode will occur if no prophylactic measures are taken. Although zidovudine will reduce the frequency of second episodes (5), some persons who receive zidovudine have been reported to have subsequent episodes. In an ongoing study of HIV-infected patients who have had a recently documented episode of PCP (AIDS Clinical Trial Group Study 002), zidovudine therapy was started using two different dosing regimens (6). The study has not yet been unblinded so that investigators can determine which patients received which zidovudine regimen. A preliminary analysis was done on the risk of recurrent PCP for 318 patients followed for up to 6 months and for 122 patients followed up to 12 months on zidovudine (Figure 2) (Panel of experts,* Fischl). These results indicate a need for PCP prophylaxis in addition to antiretroviral therapy. REGIMENS FOR PROPHYLAXIS

The two compounds studied most extensively for prophylaxis against PCP have been trimethoprim-sulfamethoxazole, given orally, and pentamidine, given as an aerosol. Trimethoprim-Sulfamethoxazole

The efficacy of trimethoprim-sulfamethoxazole for prophylaxis against PCP has been clearly demonstrated among pediatric cancer patients (7-8). The only reported randomized controlled trial of this drug combination for HIV-infected persons was a primary-prophylaxis study of 60 adult AIDS patients with Kaposi sarcoma, and compared the effect of no treatment with that of a regimen of 160 mg trimethoprim plus 800 mg sulfamethoxazole twice daily plus 5 mg leucovorin calcium once daily (9). Compared with untreated patients, those who received prophylaxis had fewer episodes of PCP and lived longer. Adverse reactions were common (50%) and included nausea, vomiting, pruritus, and rash, although these reactions also occurred commonly among patients who were not receiving trimethoprim-sulfamethoxazole. Only five patients (17%) had to discontinue prophylaxis. There are no results from controlled trials currently available for analysis to indicate whether trimethoprim-sulfamethoxazole would be effective or tolerated in other populations of HIV-infected patients. Aerosol Pentamidine

Clinical studies of aerosol pentamidine for prophylaxis against PCP have been completed by two pharmaceutical sponsors. These studies have used different nebulizing devices and different dosing regimens.

In July 1987, a randomized, nonblinded dose-comparison study of aerosol pentamidine was begun in 14 community treatment centers (10). The trial was open to adult patients who had already had PCP (secondary prophylaxis) as well as patients with Kaposi sarcoma and other symptomatic HIV-associated conditions who had never had PCP (primary prophylaxis). Patients were randomly assigned to three dose schedules: 30 mg every 2 weeks, 150 mg every 2 weeks, or 300 mg every 4 weeks of pentamidine delivered by the Respirgard II jet nebulizer (Marquest, Englewood, CO). An interim analysis 1 year after the start of randomization (mean follow-up of 10months) showed that 76 PCP episodes (13 first episodes and 63 recurrent episodes) had occurred: 33/135 (24%) in the 30-mg group, 25/134 (19%) in the 150-mg group, and 18/139 (13%) in the 300-mg group. For patients receiving secondary prophylaxis, the regimen of 300 mg every 4 weeks was associated with substantially fewer episodes of PCP than the regimen of 30 mg every 2 weeks. There are insufficient data currently available from patients receiving primary prophylaxis to demonstrate statistically significant treatment effects among the regimens.

The most common adverse effects during treatment were cough and, less frequently, wheezing--particularly among smokers and patients with a history of asthma. These effects could be reduced or prevented by pretreatment with inhaled bronchodilators. No systemic toxicity of the type associated with parenteral pentamidine (e.g., renal insufficiency, hypoglycemia, or neutropenia) was detected, although other reports suggest that systemic adverse effects can occur. Patients tolerated the therapy well with supervision, and only two had withdrawn because of side effects at the time the interim analysis was done.

On the basis of these interim results and existing epidemiologic data from natural-history studies, the Food and Drug Administration approved a treatment IND for aerosol pentamidine as both primary and secondary prophylaxis, recommending the 300-mg dose every 4 weeks and recommending delivery via the Respirgard II jet nebulizer. The indication for primary prophylaxis in the treatment IND is a CD4+ count of less than 200/mm3. Secondary prophylaxis is indicated for anyone who completes therapy for an episode of PCP.

Other nebulizers have been used in trials of aerosol pentamidine prophylaxis. A double-blinded, placebo-controlled randomized multicenter trial has recently been conducted in Canada which assessed the safety and efficacy of aerosol pentamidine administered by a Fisons ultrasonic nebulizer (five 60-mg loading doses followed by biweekly doses of 60 mg). These findings have been submitted to the FDA. A study using the Fisons nebulizer and three different doses of aerosol pentamidine has also been completed in the United States and is currently being evaluated. RECOMMENDATIONS

On the basis of the data summarized above and the opinions of individual members of the panel of experts, the Public Health Service recommends that--unless contraindications exist--physicians should initiate prophylaxis against PCP for any HIV-infected adult patient who has already had an episode of PCP, even if the patient has been receiving zidovudine. Unless contraindicated, prophylaxis should also be initiated for HIV-infected patients who have never had an episode of PCP if their CD4+ cell count is less than 200/mm3 or if their CD4+ cells are less than 20% of total lymphocytes. Patients with CD4+ cell counts of less than 100/mm3 or CD4+ cells less than 10% and patients with oral thrush or persistent fever (temperature of greater than 100 degrees F) are at particularly high risk for PCP. Patient Evaluation For HIV-infected persons, CD4+ lymphocyte percentages or counts should be monitored at least every 6 months. Some experts prefer to obtain a second count within a few months of the first count to assess the rate of decline. Subsequent CD4+ enumerations may be desirable at intervals of less than 6 months in certain situations such as: a) the presence of fever or thrush, b) a recent rapid decline in CD4+ cell count, c) a CD4+ percentage in the 20-30 range, or d) a CD4+ absolute number in the 200-300/mm3 range. If a decision to start prophylaxis is to be made on the basis of a low CD4+ cell count or percentage, the CD4+ enumeration should probably be repeated, unless previous determinations indicate the low count or percentage is consistent with an established trend.

Some patients may have discordant CD4+ percentages and absolute counts, i.e., the percentage may be greater than 20% while the CD4+ count may be less than 200/mm3, or vice versa. In such cases, it is probably prudent--after reconfirming the CD4+ enumerations--to assume that the patient is at high risk for PCP if either of these two parameters is in the high-risk range.

Clinicians should be aware that in certain unusual circumstances, either the absolute CD4+ count or the CD4+ percentage may not be an accurate reflection of susceptibility to PCP. For example, after splenectomy, HIV-infected patients may be susceptible despite normal CD4+ counts. Conversely, some laboratory reagents may not detect CD4+ markers on the T-helper cells of all persons (11), so that such persons may speciously appear to be in the susceptible range. In situations in which this phenomenon is suspected (e.g., when the sum of the number of CD4+ cells and CD8+ cells does not approximately equal the number of CD3+ cells), the lymphocyte sample should be retested with other CD4+ reagents.

Before prophylaxis against PCP is administered, patients must be evaluated to exclude certain active pulmonary diseases. If symptoms, signs, or radiologic abnormalities suggest that active disease is present, a thorough evaluation for community-acquired pathogens (e.g., Pneumococcus), opportunistic pathogens (e.g., Pneumocystis, cytomegalovirus), communicable pathogens (e.g., Mycobacterium tuberculosis), tumors, or other processes is indicated. As with other HIV-infected persons, these patients should be given a Mantoux skin test with 5-TU tuberculin, PPD (12). Choice of Prophylactic Agent Scientific studies available to date suggest the following two approaches are effective and safe, although neither has been approved as labelling indications by the Food and Drug Administration.

1. Although it has been studied less extensively among HIV-infected persons than aerosol pentamindine, oral trimethoprim-sulfamethoxazole (160 mg trimethoprim and 800 mg of sulfamethoxazole) can be given twice daily with 5 mg leucovorin once daily. This form of prophylaxis should not be given to patients with a history of type-I hypersensitivity (angioedema or anaphylaxis) or prior episodes of Stevens-Johnson syndrome associated with sulfonamides or trimethoprim. The efficacy of leucovorin in prevention of toxicity is unknown.

2. Aerosol pentamidine can be given as 300 mg every 4 weeks via the Respirgard II jet nebulizer. The dose should be diluted in 6 ml of sterile water and delivered at 6 liters/minute from a 50-PSI compressed air source until the reservoir is dry. (Further information can be obtained by telephoning the Treatment IND number: 1-800-727-7003.) Because other doses and aerosol delivery systems have not yet been adequately studied and analyzed, no recommendations regarding such systems can be made. For patients who develop cough or wheezing while receiving aerosol pentamidine, pretreatment with a bronchodilator can be tried before the aerosol therapy is given again. Patients with asthma or an extensive history of smoking may not tolerate this form of therapy, and it may not be prudent treatment for a patient with a prior life-threatening reaction to parenteral pentamidine.Since neither aerosol pentamidine nor oral trimethoprim-sulfamethoxazole prophylaxis is known to be safe in association with pregnancy, it is inadvisable to give either agent to HIV-infected pregnant women. Rather, such women should be monitored carefully for symptoms, signs, or laboratory abnormalities suggestive of PCP. Prophylaxis can then be considered for use in the postpartum period. Careful monitoring is also indicated for patients intolerant of aerosol pentamidine and trimethoprim-sulfamethoxazole, or for those unwilling to receive prophylaxis.Alternative regimens that are of unproven efficacy and safety for humans, but tha might be considered for prophylaxis, include dapsone (daily or weekly), dapsone plus trimethoprim (daily or weekly), or dapsone plus pyrimethamine (daily or weekly) and pyrimethamine-sulfadoxine (weekly). Follow-Up of Patients Receiving Prophylaxis

Since none of the regimens has been shown to be completely protective against PCP for HIV-infected persons, patients who receive prophylaxis should be monitored closely for evidence of PCP, as well as other pulmonary infections. If prophylaxis is discontinued, the patient will again be at increased risk for developing PCP.

Prophylaxis failures have been reported in which persons given aerosol pentamidine, especially at low doses, later had PCP in the upper lobes of the lung (13). In addition, prophylaxis using aerosol pentamidine does not offer protection against extrapulmonary pneumocystosis (14). Prophylaxis for Infants and Children Pneumocystis carinii pneumonia is a common manifestation of pediatric AIDS. Most experts agree that some form of prophylaxis is warranted for HIV-infected pediatric patients who are at high risk for PCP on the basis of criteria that are analagous to those described above for adults. However, there are insufficient data about the efficacy or toxicity of prophylactic regimens for pediatric patients, so that no scientifically validated guidelines can be provided as yet. There are no data concerning the appropriate dose or delivery system of aerosol pentamidine for infants or children. The appropriate dose of trimethoprim-sulfamethoxazole prophylaxis might be estimated from trials involving pediatric cancer patients (e.g., trimethoprim 75 mg/M2 plus sulfamethoxazole 375 mg/M2 given orally every 12 hours) (7,8). Further Information

Several studies are under way to gain additional information about prophylaxis against PCP. Information about these studies can be obtained from the National Institute of Allergy and Infectious Diseases Information Office (1-800-TRIALS-A) or the American Foundation for AIDS Research (212-333-3118). EDITORIAL COMMENTARY

These guidelines for prophylaxis against PCP indicate a medical benefit from the careful clinical and immunologic monitoring of persons infected with HIV and have several important implications. First, the guidelines are likely to increase the demand for HIV antibody testing by persons who believe they may be at risk for infection. The Public Health Service has estimated that between 945,000 and 1.4 million persons in the United States are infected with HIV (15). Of these persons, CDC estimates that approximately 120,000 have been informed of their infection status as a result of voluntary antibody testing carried out in public (primarily Federally funded) HIV counseling and testing centers. The number of persons found through other sources of testing to be infected is unknown, but it is likely that many persons who are infected are not aware of their infection. Persons at risk who have not had HIV antibody testing should now consider such testing because they may be candidates for prophylaxis against PCP if they are found to be infected.

Second, the guidelines are likely to increase the demand for medical services by asymptomatic HIV-infected persons. Such persons will need medical evaluation to determine whether they are candidates for prophylaxis against PCP, and--if prophylaxis is given--these persons will need medical follow-up. All persons found to be infected at HIV counseling and testing centers should be referred for further medical evaluation, including a measurement of their CD4+ cells. Facilities offering HIV counseling and testing should develop referral networks of medical-care providers sufficient to evaluate and care for the infected persons they identify. These networks should include services related to family planning and treatment for intravenous drug addiction, sexually transmitted disease, and tuberculosis. Third, the guidelines are likely to increase the demand for flow-cytomet ry services to quantify CD4+ cells from HIV-infected persons. Laboratories to which samples are referred for flow cytometry should have prior experience, since methodology can greatly influence the quality of test results. Although there are no true reference standards for evaluating blood cells, quality can be assured by adhering to criteria that address sample collection, preparation, instrument calibration and standardization, flow cytometric analysis, and adequate training of operators (16). Either absolute CD4+ counts or percentage CD4+ cells can be used in monitoring HIV-infected persons. There appears to be less day-to-day fluctuation in percentage of CD4+ cells compared with absolute number, suggesting that the former measure may be more reliable (4,17). This finding is not unexpected since the percentage of CD4+ cells is directly measured by flow cytometry, whereas the absolute number is calculated from the absolute and differential white-blood-cell count and the percentage of CD4+ cells.

Fourth, health-care providers who administer aerosol pentamidine as prophylaxis against PCP should be aware of several occupational safety issues. In particular, they should note the recommendation to exclude active pulmonary disease before starting prophylaxis. A recent investigation of M. tuberculosis infections among the staff members of a health clinic in Florida suggested that one source of infection may have related to the use of aerosol pentamidine treatment for two patients who had positive sputum cultures for M. tuberculosis during the time they received aerosol pentamidine. One of these two patients coughed profusely both during and after therapy (18). Providers administering aerosol pentamidine should also review the manufacturer's instructions for the use of the nebulizer system. The Respirgard II nebulizer contains a filter designed to remove most of the pentamidine from exhaled gases. If the nebulizer is improperly used, substantial amounts of pentamidine can be released into the environment, and health-care workers or others in the vicinity may be at risk for the same adverse events as the patients who received the therapy (19).

References

1. Sattler FR, Cowan R, Nielsen DM, Ruskin J.

Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a prospective, noncrossover study. Ann Intern Med 1988;109:280-7.

2. 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.

3. Polk BF, Fox R, Brookmeyer R, et al. Predictors of acquired immunodeficiency syndrome developing in a cohort of seropositive homosexual men. N Engl J Med 1987;316:61-6.

4. Masur H, Ognibene FP, Yarchoan RY, et al. CD4 counts as predictors of opportunistic pneumonias in human immunodeficiency virus infected individuals. Ann Intern Med (in press).

5. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled study. N Engl J Med 1987;317:185-91. 6. National Institute of Allergy and Infectious Diseases, USA. The safety and efficacy of two doses of zidovudine in the treatment of patients with AIDS. (Abstract) IV International Conference on AIDS. Book 2. Stockholm, June 12-16, 1988:168.

7. Hughes WT, Kuhn S, Chaudhary S, et al. Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 1977;297:1419-26.

8. Hughes WT, Rivera GK, Schell MJ, Thornton D, Lott L. Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonia. N Engl J Med 1987;316:1627-32.

9. Fischl MA, Dickinson GM, La Voie L. Safety and efficacy of sulfamethoxazole and trimethoprim chemoprophylaxis for Pneumocystis carinii pneumonia in AIDS. JAMA 1988;259:1185-9. 10. Leoung GS, Montgomery AB, Abrams DA, et al. Aerosol pentamidine for Pneumocystis carinii pneumonia (PCP): a randomized trial of 439 patients. (Abstract) IV International Conference on AIDS. Book 1. Stockholm, June 12-16, 1988:419. 11. Bach M-A, Phan-Dinh-Tuy F, Bach J-F, et al. Unusual phenotypes of human inducer T cells as measured by OKT4 and related monoclonal antibodies. J Immunol 1981;127:980-2.12. CDC. Tuberculosis and human immunodeficiency virus infection: recommendations of the Advisory Committee for the Elimination of Tuberculosis (ACET). MMWR 1989;38:236-8,243-50. 13. Abd AG, Nierman DM, Ilowite JS, Pierson RN, Lomis Bell AL. Bilateral upper lobe Pneumocystis carinii pneumonia in a patient receiving inhaled pentamidine prophylaxis. Chest 1988;94:329-31. 14. Poblete RB, Rodriguez K, Foust RT, Reddy KR, Saldana MJ. Pneumocystis carinii hepatitis in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989;9:737-8.15. CDC. Human immunodeficiency virus infection in the United States: a review of current knowledge. MMWR 1987;36(suppl S-6):1-48. 16. Kidd PG, Vogt RF Jr. Report of the workshop on the evaluation of T-cell subsets during HIV infection and AIDS. Clin Immunol Immunopathol 1989 (in press). 17. Taylor JMG, Fahey JL, Detels R, Giorgi JV. CD4 percentage, CD4 number, and CD4:CD8 ratio in HIV infection: which to choose and how to use. J AIDS 1989;2:114-24. 18. CDC. Mycobacterium tuberculosis transmission in a health clinic--Florida, 1988. MMWR 1989;38:256-64. 19. LyphoMed, Inc. A treatment IND for the use of aerosolized pentamidine in HIV-infected individuals at high risk for Pneumocystis carinii pneumonia. Rosemont, Illinois: LyphoMed, Inc., 1989. *Henry Masur, M.D., National Institutes of Health (Chairman); Carmen Allegra, M.D., National Cancer Institute; Donald Armstrong, M.D., Memorial Sloan-Kettering Cancer Center; Victor DeGruttola, D.Sc., Harvard University Statistical Center; Susan S. Ellenberg, Ph.D., National Institute of Allergy and Infectious Diseases; David Feigal, M.D., San Francisco General Hospital; Judith Feinberg, M.D., National Institute of Allergy and Infectious Diseases; Margaret A. Fischl, M.D., University of Miami School of Medicine; Walter T. Hughes, M.D., St. Jude Children's Research Hospital; Harold Jaffe, M.D., Centers for Disease Control; John Mills, M.D., San Francisco General Hospital; A. Bruce Montgomery, M.D., SUNY at Stony Brook; Alvaro Munoz, Ph.D., Johns Hopkins School of Public Health; John P. Phair, M.D., Northwestern University Medical School; Frank Richards, M.D., Yale University; Fred Sattler, M.D., University of Southern California; Gerald Smaldone, M.D., Ph.D., SUNY at Stony Brook; Carol Braun Trapnell, M.D., Food and Drug Admiistration; Sten H. Vermund, M.D., M.Sc., National Institute of Allergy and Infectious Diseases. Consultants to the Task Force were Judith Falloon, M.D., National Institutes of Health; Michael Polis, M.D., M.P.H., National Institutes of Health; Michael Sampson, M.D., SUNY at Stony Brook.

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