Patients at Risk for Pneumocystis carinii Pneumonia

Asymptomatic primary infection from P. carinii usually occurs in childhood, with pneumonia occurring from recrudescence in the setting of immunosuppres-sion. Historically, the PCP usually occurred in settings of immunosuppression from either childhood malnutrition, chemotherapy, or congenital immunodeficiencies [26,27]. The overwhelming current cause for immunosuppression is infection from the human immunodeficiency virus (HIV). In people infected with HIV, significant risk for PCP can be quantified by the presence of other opportunistic infections, by symptoms, or by the CD4 lymphocyte count [2830]. The most obvious and highest-risk group for PCP is patients who have experienced a prior episode; prophylaxis in this group is called secondary prophylaxis. The risks of recurrent PCP have been assessed by historical case control studies and ongoing clinical trials of zidovudine (Table 2) [31,32]. Analysis of 201 consecutive patients with first-episode PCP at San Francisco General Hospital (SFGH) in the prezidovudine era has shown that of the 61 (30%) who relapsed with PCP, 18% did so at 6 mo, 46% at 9 mo, and 65% at 18 mo [31]. Hence, most patients with a second episode of PCP are expected to relapse within 18 mo. Although zidovudine does decrease the risk of PCP slightly, the incidence of PCP over time does not differ greatly in patients taking zidovudine from the SFGH historical controls (Table 2) [33]. In fact, the absolute incidence of recurrent PCP in patients taking zidovudine may have been increased because of longer survival times [33,34].

Identification of HIV-infected individuals at high risk for PCP who have not had an initial bout is more problematic. At least 20% of AIDS patients will never have an episode of PCP, and the number of HIV-infected individuals is large compared to those who have had PCP. Nevertheless, both clinical and immunological status, have been used to determine risk. The initial determinants of risk were case reviews of patients presenting with PCP [28]. In addition to having prodromal symptoms, these patients commonly experience weight loss, hairy leukoplakia, and mucocutaneous candidiasis. In these persons, PCP usually occurs when an absolute CD4 lymphocyte count normally between 800 and 1,000 cells/mm3 decreases to less than 200 cells/mm3 [28,29]. These studies could not determine what percentage of unprophylaxed HIV-infected patients with similar symptoms and immuno-logical status would develop PCP. Recently, however, in the Multicenter AIDS Cohort Study (MACS) of 1,660 homosexual males, the incidence of PCP with a baseline of less than 200 CD4 cells/mm3 was more than 1% a month in the first year (Table 2) [30]. The initial occurrence rate of PCP among persons with a baseline CD4 count between 201 and 350 CD4 cells/mm3 was low, this may reflect a real finding or a referral bias of relatively healthy survivors into the study. The CD4 lymphocyte count of less than 200 cells/mm3 is not infallible in the MACS study or other studies. For example, in a prospective trial of TMP-SMX, in the placebo arm of patients with Kaposi's sarcoma, 3 of 16 developed PCP with a CD4 count of greater than 200 cells/mm3 [29]. The MACS study also confirmed that fever, oral candidiasis, and weight loss were independent factors for increased risk of PCP [30].

Aerosolized Pentamidine

Aerosolized pentamidine prophylaxis has been studied in two large clinical trials in North America and in one large trial in Europe. The first trial was the San Francisco Community Consortium study conducted by Leoung and colleagues, who observed 408 patients with either prior PCP (n = 250), Kaposi's sarcoma (n = 59), or other AIDS-related diagnosis or complex (n = 129). Patients were randomized to receive either 30, 150, or 300mg aerosolized pentamidine using the Respirgard II nebulizer system [35]. The 30- and 150-mg doses were administered every 2 wk; the 300-mg dose was given every 4 wk. Pentamidine at a dose of 300 mg every 4 wk was significantly better than 30 mg given biweekly in three analyses: intention to treat, analysis of patients on drug, and analysis of patients on drug with histological confirmation of PCP. The regimen consisting of 300 mg every 4 wk also tended to be superior than that of 150 mg every 2 wk. The study was conducted for 18 months, with a mean follow-up approaching 1 yr [35] (Table 3).

The second study was a double-blinded comparative trial of secondary prophylaxis comparing 60 mg aerosolized pentamidine given every 2 wk after five weekly loading bases to placebo using a handheld FisoNeb ultrasonic nebulizer with a 5-p.m MMAD particle size [36,37]. The study was intended to run 6 mo, but it was terminated early, with a mean follow-up of only 3.7 mo. Aerosolized pentamidine significantly reduced the reoccurrence rate of PCP as compared to controls in this study [37,38].

Comparing the relapse rate of the 60-mg dose given every 2 wk after four weekly loading doses in the second study to the 300-mg dose given every 4 wk in the first study would best be done by a prospective trial. However, in the patients with one episode of PCP, the life table reoccurrence rate at 6 mo with the 60-mg regimen using the FisoNeb nebulizer was 10%, compared to 4% with the 300-mg regimen using the Respirgard II nebulizer, suggesting an advantage to the 300-mg regimen [37]. Because of the short duration of the second study, no longer-term comparisons could be made at that time.

Based on these data, the Food and Drug Administration (FDA) approved the 300-mg dose of pentamidine delivered by the Respirgard II nebulizer every 4 wk as PCP prophylaxis in any HIV-infected patient with a prior episode of PCP or a CD4 count of less than 200 cells/mm3. The San Francisco study did not prove a dose response in the primary-prophylaxis patients, most likely because of the small numbers of events, but the trends parallel the secondary-prophylaxis group. The FDA approval for primary prophylaxis was based on inference, accepting proven efficacy in secondary prophylaxis, proven safety in primary prophylaxis, and recognizing recent studies documenting significant PCP risk in HIV-infected patients with low CD4 cell counts [37].

Table 3 Kaplan-Meier Estimates of Proportion with PCP in HIV-infected Persons

Cumulative (%)

Table 3 Kaplan-Meier Estimates of Proportion with PCP in HIV-infected Persons

Ref.

Study group

Prophylactic drug

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