THE OI REPORT: A Critical Review of the Treatment & Prophylaxis of AIDS-Related Opportunistic Infections (OIs)

PNEUMOCYSTIS CARINII PNEUMONIA (PCP)
by Michael Marco

INTRODUCTION
In a retrospective analysis of HIV-positive patients with Pneumocystis carinii pneumonia (PCP), Masur and colleagues noted that the immunologic threshold for almost all the patients was a CD4 count of less than 200. Most of the cases, however, were noted in patients with CD4 counts less than 100 (Masur 1989).

From a cohort of 1665 HIV-positive men from the Multicenter AIDS Cohort Study (MACS), Phair and colleagues documented that the risk of developing PCP within six months of having a CD4 count below 200 was 6% compared to 0.5% for those with CD4 counts between 200 and 350. For those with CD4 counts below 200, the risk of developing PCP within 12 months was 20.7% and within three years, approximately 38%. This study also found that persistent, unexplained fever or thrush significantly and independently increased the risk for developing PCP in HIV-positive patients regardless of their CD4 count (adjusted relative risks, 1.86 and 2.15 for thrush and fevers, respectively) (Phair 1990).

More MACS data revealed that combining antiretroviral therapy with PCP prophylaxis decreases the incidence of PCP (Bacellar 1994). In 2,646 patients with less than 100 CD4 cells, the incidence rate of PCP in patients who were on neither was 47.4%, 21.5% in patients on PCP prophylaxis only and 12.8% when patients combined antiretroviral therapy with PCP prophylaxis. Because patients from 1985 to 1993 had only AZT and ddI available to them, it might be safe to assume that more potent antiretroviral regimens would further decrease the incidence of PCP. Since the wide-spread use of potent protease inhibitor conmbination therapy (PPICT), the incidence of PCP appears to have declined to between 2.5% and 11.7% (Currier 1997;Michaels 1997).

Widespread use of PCP prophylaxis has changed the natural course of HIV infection. Because patients are able to stave off PCP with the use of prophylaxis, many are now open to various other opportunistic infections, which have increased in incidence. This was amply documented in Donald Hoover's seminal MACS paper, "Clinical Manifestations of AIDS in the era of PCP Prophylaxis" (Hoover 1993). From a MACS sub-cohort of 844 men, Hoover revealed that since the widespread use of PCP prophylaxis, four OIs have become more common: Mycobacterium avium, wasting syndrome, cytomegalovirus, and esophageal candidiasis.

(Hoover 1993)

These data were from before the era of rifabutin, clarithromycin, or azithromycin for MAC prophylaxis. Nevertheless, Hoover postulated, "[PCP] prophylaxis may delay the first AIDS illness for 6 to 12 months." Very few patients develop MAC above 75 CD4 cells or CMV above 50. Before widespread PCP prophylaxis and the development of effective treatment regimens, many patients did not live long enough to reach such low CD4 levels.

Recent Centers for Disease Control and Prevention (CDC) data on 8,622 patients show that both trimethoprim-sulfamethoxazole (Bactrim) and dapsone prophylaxis are associated with increased survival. Ward and colleagues from the CDC's Adult/Adolescent Spectrum of Disease study correlated survival with treatment patterns by reviewing medical records of persons diagnosed with AIDS from 1990 to 1994. The median survival for people with AIDS (PWAs) was 35 months (95% CI, 33-36 months). After controlling for CD4 count, age and risk, antiretroviral treatment, Bactrim, dapsone (but not aerosolized pentamidine) as well as MAC prophylaxis with either rifabutin or clarithromycin, were associated with improved survival.

(Ward 1995)

Persons on antiretroviral treatment, PCP and MAC prophylaxis lived the longest (47 months, 95% CI, 44-52 months).

Who is Not Receiving PCP Prophylaxis?
While a vast majority of AIDS physicians institute PCP prophylaxis in their patients when a CD4 count goes below 200, many HIV-positive patients are still developing PCP. The reasons for this were suggested by Sandra Schwarcz and colleagues from the San Francisco Department of Public Health. They reviewed 321 case records of patients residing in San Francisco whose AIDS-defining diagnosis was PCP in 1993. Only 35% had received PCP prophylaxis. The study concluded that:

• Non-whites were significantly less likely to have received primary (first episode) PCP prophylaxis than were white patients (23% versus 40%, respectively; p=0.03).
• Individuals who lacked health insurance were less likely to have received primary PCP prophylaxis than were individuals who had health insurance (16% versus 41%, p=0.001).
• There were no sociodemographic differences in secondary prophylaxis use.
• The most common reasons cited by patients for not seeking PCP prophylaxis were lack of awareness of their HIV infection or lack of regular medical care (Schwarcz 1995).

This study addressed a significant problem for many at risk of HIV, especially those from at-risk communities. Many of these individuals do not have access to health insurance, and many more do not know they are HIV-positive until their first bout of PCP. Vastly increased education about testing and PCP prophylaxis might help prevent many individuals from developing PCP and possibly dying from it.

Incidence Trends in AIDS-Related Deaths
In the 1980s, retrospective studies documented that between 45.5% and 64% of patients with severe PCP died from it (Effren 1989; Friedman 1989). As the understanding of the disease increased and treatment regimens improved, the rate drastically dropped. This is evident in a CDC study conducted by Selik and colleagues on the changing mortality trends in AIDS from 1987 to 1992 (Selik 1995). Based on analyses of death certificates documenting HIV infection and any OI listed in more than 1% of cases, Selik noted that mortality due to PCP had decreased by more than half in five years. Below is a listing of various causes of death:

(Selik 1995)

In 1997, the death rate decreased markedly because of potent protease inhibitor combination therapy (PPICT). Yet, before powerful antiviral therapy was available, the wide-spread use of PCP prophylaxis dramatically altered overall causes of AIDS mortality between the late 1980s and 1990s.

BIOLOGY OF PCP
Pneumocystis carinii has historically been classified as a protozoal organism (Limper 1991). Its taxonomic classification as a protozoan, however, appears to be uncertain; some think it is a fungus. Edman and colleagues asserted on the basis of ribosomal RNA sequence comparisons that P. carinii is a member of the fungi (Edman 1988). Stringer and colleagues also found more genetic similarity to fungi (Saccharomyces cerevisiae, Neurospora crassa, Candida albicans, and Cryptococcus diffuens) than to protozoal sequences (Stringer 1989). Clinically, however, P. carinii is susceptible to antiprotozoal rather than antifungal therapy.

DIAGNOSIS
P. carinii cannot be cultured and there are presently no antigen or antibody assays that can be used for diagnosis (Dohn & Frame 1997).

Signs & Symptoms
The most typical presenting symptoms of PCP in HIV-positive patients are a non-productive cough, labored breathing on exertion or at rest, and fever. The onset of illness is often a subtle one, during which many of these symptoms can persist for weeks.

Patients with suspected PCP are usually asked to undergo a standard test called arterial blood gas (ABG), which measures the oxygen content in blood. Patients with PCP have an increased alveolar-to-arterial (A-a) O2 gradient, because the proper amount of oxygen is unable to pass from the alveolar (lungs) into the arterial (blood). Patients with abnormally low concentrations of oxygen in the blood are considered to have hypoxemia. Serum lactate dehydrogenase levels (LDH, an enzyme) may also be elevated.

Definitive Diagnosis
Definitive diagnosis requires an X-ray and histological (tissue) or cytological (cell) evidence of P. carinii on bronchoalveolar lavage (BAL), lung biopsy or sputum specimen. A chest x-ray usually shows bilateral, diffuse interstitial infiltrates (small, wide-spread patches of P. carinii in the lungs). On occasion, the infiltrates are unilateral, asymmetric, or focal. "Virtually every possible chest radiographic finding has been seen in patients with Pneumocystis." (Huang 1996). A normal chest X-ray is not uncommon in patients with localized disease (especially upper lobe infiltrates). In an ongoing San Francisco General Hospital (SFGH) study, almost 10% of cases presented with a normal chest X-ray (Huang 1996).

Sputum induction for diagnosis is often difficult, and many centers have been unable to attain a high sensitivity (Dohn 1997). A bronchoscopy where BAL is obtained is considered to be the diagnostic procedure of choice. It is more than 90% sensitive for PCP (Stover 1984). When the induced sputum test comes back negative, BAL can help to confirm the diagnosis. At SFGH, Huang and colleagues reviewed approximately 400 cases in which sputum induction for PCP was performed. In 50% of the cases, the bronchoscopy with BAL confirmed a PCP diagnosis after a negative induced sputum. In the other cases, BAL detected other undiagnosed pulmonary complications mimicking PCP, including tracheobronchial Kaposi's sarcoma (KS), tuberculosis and Cryptococcus neoformans pneumonia (Huang 1995).

AIDS PCP tends to have a higher pathogen count than non-AIDS PCP, according to Limper and colleagues, who quantitated PCP organisms in BAL from a case series of 75 AIDS and non-AIDS PCP patients (p<0.0001) (Limper 1991).

Polymerase chain reaction (PCR) assays for diagnosis have generated much attention over the past few years. PCR is 85 to 100% specific and sensitive (Atzori 1995; Contini 1995). This approach has not been adequately validated, however, and is not yet available for routine use.

PROGNOSTIC FACTORS
The severity of PCP is based on a patient's (A-a) O2 gradient which measures the ratio of alveolar (lung) oxygen to arterial (blood) oxygen. Numerous studies indicate that an (A-a) O2 gradient of 35 mm Hg or greater places a patient at higher risk for adult respiratory distress syndrome (ARDS; respiratory failure requiring mechanical ventilator) and early mortality (Brenner 1987; Benson 1991). Brenner and colleagues documented that severe abnormalities on an initial chest radiograph, and alveolar-arterial oxygen differences (Aa-O2) greater than 30 mm Hg were associated with higher mortality during the period of treatment for the acute episode (p<0.05). Likewise, decreased long-term survival after the diagnosis of PCP correlated with the severity of interstitial edema (fluid caught in the lungs) on initial transbronchial biopsy and elevation of AaPO2 at diagnosis (Brenner 1987). A rising LDH level on therapy may indicate worsening pulmonary function and treatment failure (Brenner 1987; Garay 1989; Benson 1991).

TREATMENT
Trimethoprim-Sulfamethoxazole (TMP/SMX / Bactrim) and intravenous (IV) pentamidine were both available for the treatment of PCP at the beginning of the AIDS epidemic. Initial studies of these agents in patients with AIDS showed a high mortality rate (Wharton 1986; Sattler 1988; Klein 1992).

TMP/SMX versus IV Pentamidine
Between 1983 and 1984, Wharton and colleagues randomized 40 AIDS patients with their first episode of PCP to receive either TMP/SMX or IV pentamidine. Five (25%) of the 20 patients treated initially with TMP/SMX and one (5%) of the 20 patients treated initially with pentamidine died during the 21-day treatment period (p=0.09). Eight patients assigned to the TMP/SMX arm stayed on treatment and 12 crossed over to pentamidine due to lack of response (n=2) or toxicities (n=10), including neutropenia, severe rash, elevated transaminase, or thrombocytopenia. Eleven pentamidine patients were switched to the TMP/SMX arm because of similar toxicities as well as uremia (kidney toxicity). Both therapies appeared equivalent in treating PCP, yet because of the small sample size, a reliable comparison was impossible (Wharton 1986).

A later study randomized 163 AIDS patients with PCP to receive either IV TMP/SMX (TMP 20 mg/kg daily plus SMX 100 mg/kg daily) or pentamidine (4 mg/kg daily). The overall survival rate was 67% and 74%, respectively (p=0.402). In the TMP/SMX arm, 39 patients (42%) required a change in therapy due to a failure to respond and 31 (34%) switched to pentamidine due to drug toxicity. No significant difference was seen in the pentamidine arm, in which 27 (40%) patients switched due to failure to respond and 17 (25%) switched due to drug-related toxicity (Klein 1992).

The third of the classic TMP/SMX versus IV pentamidine studies was conducted by Sattler and colleagues. This study, however, was the first prospective noncrossover study to be completed as well as the first to show a response and survival difference. Thirty-three of the 36 TMP/SMX patients and 27 of the 34 IV pentamidine patients were being treated for their first PCP episode. All 36 TMP/SMX patients completed the study as did 33 of the 34 pentamidine patients without crossover. To adjust for excessive blood levels of TMP/SMX, patients receiving 15 to 20 mg/kg daily of TMP and 75 to 100 mg/kg daily of SMX in three equally divided doses had their TMP dose titrated down to 12 mg/kg daily. And in adjusting for possible renal impairment with pentamidine, patients would have the initial dose of 4 mg/kg daily reduced by 30 to 50%. Rash occurred more frequently in the TMP/SMX arm (44% versus 15%; p=0.001), as did anemia (39% versus 24%; p=0.03). Pentamidine patients had more days of drug-induced fever (8 days versus 5 days; p=0.04) and a higher rate of nephrotoxicity (64% versus 14%; p<0.0001). Dosage reductions occurred on 36 occasions in 25 TMP/SMX patients and in 8 pentamidine patients. TMP/SMX induced a better clinical response, with normalization of temperatures (p=0.08) and an (A-a) O2 improvement by greater than 10 mm Hg 8 days earlier (p=0.04). TMP/SMX patients also lived longer. Of all patients treated with TMP/SMX, 86% were alive (and without respiratory support) as compared with 61% of the pentamidine patients (p=0.03) (Sattler 1988).

Dapsone-Trimethoprim
Between 1984 and 1985, Leoung and colleagues at SFGH evaluated oral dapsone-trimethoprim in a small open-label pilot study of 15 patients with mild-to-moderately severe PCP. All patients given dapsone (100 mg daily) plus trimethoprim (20 mg/kg daily) improved clinically and radiographically within 3 to 10 days. Thirteen of the 15 patients completed therapy and all 15 survived. Side effects, including nausea, rash, elevated transaminase, or anemia occurred in 14 patients, yet only 2 patients required stopping therapy (Leoung 1986).

One year later, the SFGH group compared TMP/SMX with dapsone-trimethoprim in a randomized, double-blind study of 60 AIDS patients with mild-to-moderately severe (PaO2 levels greater than 60 mm Hg) first episodes of PCP. Thirty patients received the same dosages of dapsone-trimethoprim used in the Leoung study, and 30 patients received 20 mg/kg daily of TMP and 100 mg/kg daily of SMX. Three TMP/SMX and 2 dapsone-trimethoprim patients switched to IV pentamidine due to severe and progressive pulmonary failure during the first 4 days of therapy. Due to toxicity, 17 (57%) of the TMP/SMX patients were switched to IV pentamidine versus 9 (30%) in the dapsone-trimethoprim arm (p<0.025). Patients in the TMP/SMX arm had a higher rate of elevated transaminase levels (p=0.05) and a trend toward more neutropenia (p=0.08). Both treatment arms were considered equivalent for response and survival; only one patient died on study (Medina 1990).

Clindamycin-Primaquine
ACTG 044, a non-randomized, uncontrolled pilot study, suggested the efficacy of clindamycin-primaquine for the treatment of mild-to-moderate PCP. All patients received 30 mg of oral primaquine for 21 days plus 900 mg of IV every eight hours for the first 10 days followed by 450 mg of oral clindamycin every 6 hours for 11 days. A marked clinical response was documented after 7 days in 20 (91%) of 22 evaluable patients. Subsequently, 4 patients withdrew in week 2 because of toxicity, 3 due to rash and low-grade fever and 1 due to neutropenia. Rash was pronounced in all patients, yet resolved after a few days while on treatment (Black 1994).

Toma and colleagues compared clindamycin-primaquine with TMP/SMX in first episode, mild-to-moderate PCP. Twenty-seven patients were randomized to receive 600 mg of IV clindamycin every six hours for 10 days followed by 450 mg orally every 6 hours for the next 11 days plus 15 mg of primaquine, and 22 received 20 mg/kg daily of TMP and 100 mg/kg daily of SMX in a blinded fashion. Of 27 clindamycin-primaquine patients, 25 (89%) survived, and 18 (66%) completed the study on their assigned drug. Twenty-one (95%) of 22 TMP/SMX patients survived and 16 (72%) completed the study in their assigned arm. While many of the toxicities in the clindamycin arm were similar to those seen in ACTG 044, the use of antihistamines helped reduce the occurrence and severity of rash (Toma 1993).

ACTG 108: TMP/SMX versus Dapsone-TMP versus Clindamycin-Primaquine
ACTG 108 compared the efficacy and toxicity of 3 oral regimens, TMP/SMX, dapsone-trimethoprim (DT) and clindamycin-primaquine (CP, 600 mg clindamycin thrice daily and 30 mg primaquine daily) in AIDS patients with mild-to-moderate PCP (PAO2-PAO2 of 35 to 45 mg Hg). With 181 evaluable patients, ACTG 108 was the largest comparative double-blind trial of these regimens. Doses of TMP/SMX and DT varied by weight. All patients with moderately severe PCP (PAO2 of 35-45 mm HG) were given 40 mg of prednisone twice daily for five days, then once daily for three weeks. Therapeutic failure was defined as an increase in PAO2-PaO2 of greater than 20 mm Hg over baseline without remission of baseline signs and symptoms, a change in anti-Pneumocystis therapy for reasons other than toxicity, intubation, or death within 60 days after stopping therapy. Of 256 patients enrolled in the study, only 181 were evaluable. 90% had no history of PCP and 67% had never received PCP prophylaxis. The mean room air PAO2-PaO2 was 27 mm HG; 30% had a PAO2-PaO2 greater than 35 mm HG.

(Safrin 1996)

While the "sample size afforded suboptimal power for detecting differences in therapeutic efficacy," it did have an "80% power to detect pair-wise differences in the rate of therapeutic failure of 20% or greater." And with an overall therapeutic success rate of 90%, ACTG 108's results compare favorably with those of many previous studies (Medina 1990; Black 1994).

Toxicities differed in the three arms. Rash was the most frequent dose-limiting toxicity: 19% for TMP/SMX; 10% for DT; and 21% for CP (p=0.2). Grade III rashes (characterized by vesication, moist desquamation, or ulceration) occurred more frequently in the CP patients: 6% for TMP/SMX; 2% for DT; and 16% for CP (p=0.07). Patients in the CP arm had significantly more hematologic toxicities. Grade III or IV anemia or neutropenia occurred in 11% of the TMP/SMX patients, 12% of the DT patients and in 28% of the CP recipients (p=0.01). Serum alanine or aspirate aminotransferase levels (liver function tests) more than 5 times the baseline levels were more frequent in the TMP/SMX arm: 19% in the TMP/SMX group; 3% in the DT group; and 7% in the CP group (p=0.003). With regard to quality of life, the CP group at day 7 reported greater health status scores compared to the TMP/SMX group (general health perception, p=0.06; pulmonary symptoms, p=0.05; and for disability, p=0.01). By day 21, however, the differences among the groups became less evident.

ACTG 108 validated all regimens for the treatment of mild-to-moderate PCP. In determining which treatment might be best for particular patients, Safrin and colleagues comment that the decision "may ultimately rest on expected toxicities rather than on anticipated differences in efficacy." (Safrin 1996).

Trimetrexate (Neutrexin™)
After a long struggle and many studies, trimetrexate was approved by the FDA for the treatment of PCP intolerant or non-responsive to TMP/SMX and IV pentamidine. In ACTG 029/031, Sattler and colleagues compared trimetrexate with leucovorin (folic acid) against TMP/SMX for 21 days in 215 patients with moderate-to-severe PCP:

(Sattler 1994)

Patients' PAO2-PaO2 improved significantly faster with TMP-SMX. While safer, trimetrexate was clearly not as effective as TMP/SMX (Sattler 1994).

Atovaquone (Mepron™, Glaxo-Wellcome)
Atovaquone (Mepron) has been approved by the FDA for the treatment of mild-to-moderate PCP in patients unable to tolerate TMP/SMX. Hughes and colleagues conducted a double-blind study which randomized 322 PCP patients to receive 750 mg of atovaquone thrice daily or TMP/SMX (320 mg/1600 mg) daily for 21 days. Of 138 evaluable atovaquone patients, 28 (20%) failed therapy as compared to 10 (7%) of the 146 evaluable TMP/SMX patients (p=0.002). Adverse effects (mostly elevated hepatic transaminases, nausea and rash) which required a change of therapy were more common in the TMP/SMX patients: 7% of the atovaquone patients versus 20% for the TMP/SMX patients (p=0.001). After 4 weeks of treatment, there were 11 deaths in the atovaquone group as compared to one in the TMP/SMX arm (p=0.003). Of note, diarrhea at entry was associated with lower plasma drug concentrations (p=0.009), therapeutic failure (p=<0.001), and death (p=<0.001) for those patients in the atovaquone group. Thus, atovaquone has fewer adverse effects, but is clearly not as effective as TMP/SMX (Hughes 1993).

Dohn and colleagues compared atovaquone to IV pentamidine in 99 patients with mild-to-moderate PCP. There was no significant difference in treatment success or mortality between the two drugs, yet more patients discontinued IV pentamidine (36%) than atovaquone (4%) due to toxicity (p<0.001) (Dohn 1994).

Both of these studies used the old, poorly water soluble atovaquone tablets which were plagued with erratic systemic absorption (Moe & Hardy 1994). The new liquid suspension form of atovaquone appears to have 30% better absorption (Falloon 1993). Thus, the new liquid suspension might be more effective than the tablet, however, there are currently no clinical data supporting its use in treating PCP.

Corticosteroids as Adjunctive Therapy
In 1990 the United States Public Health Service (USPHS) and the National Institutes of Health (NIH) recommended the use of corticosteroids as adjunctive therapy for patients with moderate-to-severe PCP (USPHS 1990). The use of coticosteriods within 72 hours of presentation of severe PCP has been shown to prevent early deterioration and dramatically reduce the mortality of many patients (Bozzette 1990; Montaner 1990). In a 333 patient controlled study, Bozzette and colleagues documented a reduction in mortality (43% to 19%) and an approximate 50% decrease in the need for intubation for those patients receiving steroids.

PROPHYLAXIS
PCP prophylaxis was the single most important improvement in the standard of care during the first ten years of AIDS. PCP prophylaxis helped significantly reduce the rate of progression to AIDS well before the advent of MAC prophylaxis, better OI treatments, and protease inhibitors.

Trimethoprim-Sulfamethoxazole (Bactrim™, Septra™, TMP/SMX)
In 1984, Fischl and colleagues were the first to conduct a comparative study of TMP/SMX for the prophylaxis of primary PCP in HIV-positive individuals. Sixty patients with newly diagnosed Kaposi's sarcoma (KS) and no other opportunistic diseases were assigned to receive 160 mg of TMP plus 800 of mg SMX (1 double strength tablet) twice daily and leucovorin (folic acid) or no prophylactic therapy.

(Fischl 1988)

Four patients who developed PCP in the TMP/SMX arm discontinued therapy discontinued due to drug toxicity. Most non-PCP-related deaths were attributed to other opportunistic disease, most notably progressive visceral KS in 12 of the patients. Adverse reactions, including rash, nausea, vomiting, fever, leukopenia and pruritus (itching) occurred in 50% of the patients. Discontinuation of therapy occurred in 17% of the TMP/SMX patients (Fischl 1988).

Aerosolized Pentamidine (AP, NebuPent™)
Hirschel and colleagues were among the first to document that aerosolized pentamidine (AP) was safe and effective for primary PCP prophylaxis in HIV-positive individuals. 223 patients with advanced AIDS-related complex (ARC) or a CD4 count less than 200 were randomized to receive 300 mg of AP or placebo with inhaling sodium isethionate every 28 days. Eight (7%) of 114 AP patients developed PCP as compared with 21% of placebo patients (p=0.0021). No significant survival difference was noted. Moderate-to-severe coughing occurred in 38 (33%) of the AP patients and in 7 (6%) of the placebo patients (p<0.00001). Four (3.5%) AP patients discontinued therapy (Hirschel 1991).

In the San Francisco Community Prophylaxis Trial, Leoung and colleagues compared three different AP regimens (30 mg every week versus 150 mg every 2 weeks versus 300 mg every 28 days) in 408 patients for primary and secondary prophylaxis. The 300 mg dose every 28 days was found to be significantly superior to the 30 mg dose with 8 confirmed episodes compared to 22 (p=0.0008). No statistical superiority was observed between the 300 mg and 150 mg doses (Leoung 1990). Nonetheless, this study was the basis for FDA approval of AP for primary and secondary PCP prophylaxis at 300 mg/month delivered with Respigard II nebulizer. Protocol statistician David Feigal later became director of the FDA Division of Antiviral Drug Products.

Two nebulizer systems deliver AP -- the Respigard II nebulizer and the Fisoneb hand-held, patient-triggered, ultrasonic nebulizer -- and both appear to be equally efficacious and have similar toxicity profiles. They have not been compared in a head-to-head study, and subsequent developments (see below) confirmed the superior efficacy of systemic PCP prophylaxis (Bactrim or Dapsone), so AP should be reserved for patients with documented repeated intolerance to these sulfa-based drugs (CDC 1992).

Before AP is used, the patient's medical history should be evaluated for the possible presence of tuberculosis (TB). Patients should also be closely monitored during AP treatment for symptoms suggestive of TB (Moe & Hardy 1994). The CDC recommends that health-care workers administering AP wear particulate respirators if they are in the room or administration booth with a patients who has been or is at high risk for TB. Likewise, AP treatment should take place in rooms or booths with negative pressure ventilation relative to adjacent areas and so the air exhausted flows outside and away from air-intake ducts (CDC 1990).

TMP/SMX versus AP
TMP/SMX was found to be superior to AP for primary prophylaxis in a 215 patient study conducted in the Netherlands. Participants with CD4 counts below 200 were randomly assigned to receive 1 double-strength tablet, 1 single-strength tablet of TMP/SMX daily or 300 mg of AP (via Respigard nebulizer) every 28 days. After a mean follow-up of 264 days, 6 (11%) of the 71 AP patients developed PCP as compared with zero in both 71 patient TMP/SMX arms (p=0.002). Discontinuation of study drug due to cough occurred in 2 AP patients whereas 17 single-strength TMP/SMX patients and 18 double-strength patients discontinued mainly due to rash. Adverse reactions occurred far sooner for the double-strength TMP/SMX patients (16 days) as compared with 57 days for the single-strength group (p=0.02) (Schneider 1992). For secondary PCP prophylaxis, ACTG 021, conducted by Hardy and colleagues, proved that TMP/SMX was superior to AP. Three hundred ten patients taking AZT were randomized to receive one double-strength tablet of TMP/SMX daily or 300 mg of AP monthly.

(Hardy 1992)

Seven patients originally assigned to TMP/SMX who continued in their arm developed PCP and 7 of them switched to AP because of adverse effect and then developed PCP. Four patients randomized to TMP/SMX and 6 AP patients developed toxoplasmosis while on study. In an on-treatment analysis, only one toxoplasmosis case developed when a patient was taking TMP/SMX. Of 57 episodes of presumed or confirmed bacterial infections, 19 occurred in the TMP/SMX arm and 38 occurred in the AP arm. Time to the first bacterial infection significantly favored the TMP/SMX group (p=0.017). With regard to survival, there was no significant difference: 43 deaths in the TMP/SMX arm and 47 in the AP arm. Likewise, median survival was 25.8 months for the TMP/SMX patients and 22.8 for the AP group (p=0.32). Toxicities, including hematologic, hepatic, rash and fever, did not differ significantly. A similar proportion of those with and without previous TMP/SMX reactions switched to AP during the study (Hardy 1992).

After the results of ACTG 021 came in, the USPHS released revised guidelines recommending the routine use of TMP/SMX (one double-strength tablet daily) as first-line PCP prophylaxis for HIV-infected individuals 6 years of age and or older; AP at 300 mg monthly was recommended as second-line prophylaxis (CDC 1992). Of note, this panel disregarded data then available (though not yet published) on the lesser toxicity of lower-dose TMP/SMX (Schneider 1992).

Dapsone
Dapsone is a safe and inexpensive alternative to TMP/SMX for patients intolerant of the latter. In 1990, a study demonstrated that oral dapsone (50-100 mg daily) looked like a good primary and secondary PCP prophylaxis in a 30 patient study (Kemper 1990). In an 86 patient head-to-head comparison of dapsone versus TMP/SMX for primary prophylaxis, both proved effective, with just one patient in each group developing PCP after 1638 patient-months of observation (Blum 1992). Rash was the most common toxicity noted in both groups. Dapsone and AP were equally effective in a 96 patient primary and secondary prophylaxis study (18% versus 17% cases of PCP, respectively). No significant differences were noted in the number of patients requiring blood transfusions, or in hemoglobin, white blood cell or platelet counts (Slavin 1992).

The efficacy of dapsone plus pyrimethamine for PCP and toxoplasmosis prophylaxis was documented in two large randomized European studies (Girard 1993; Mallolas 1993). In one of them conducted by Girard and colleagues, 176 patients were randomized to receive AP and 173 to receive 50 mg of dapsone daily plus 50 mg of pyrimethamine weekly (DP). After a 539 days, the intent-to-treat analysis revealed 10 cases of PCP in both groups, but found 32 (18.2%) cases of toxoplasmosis on AP versus 19 (11%) on DP. The risk of developing PCP in both groups was similar, yet a higher rate of toxoplasmosis (RR 1.81) was seen in the AP arm (p=0.02). For patients with serologic evidence of past exposure to Toxoplasma gondii, the relative risk of symptomatic toxoplasmosis was 2.37 times higher for those assigned to AP (p=0.006). Because of toxicity (mostly rash), more dapsone-pyrimethamine patients than AP patients discontinued therapy: 43 versus 3, respectively (p=0.001) (Girard 1993)

Atovaquone (Mepron™, Glaxo Wellcome)
In 1997, data from two randomized controlled PCP prophylaxis studies employing atovaquone oral suspension were presented: one versus dapsone, the other versus AP. Terry Beirn Community Program for Clinical Research on AIDS (CPCRA) 034/ACTG 277 was designed to compare the efficacy and safety of daily dapsone (100 mg tablet) versus daily atovaquone (1,500 mg suspension) for the prevention of PCP in HIV-positive individuals intolerant to TMP/SMX (El-Sadr 1997b). Those randomized to dapsone who had CD4 counts less than 100 with positive toxoplasmosis serology were recommended to take weekly pryrimethamine and folic acid for toxoplasmosis prophylaxis. All patients who developed PCP or experienced toxicity that warranted discontinuation of study drug were allowed to switch treatment arms at the clinician's discretion.

A total of 1,057 patients were enrolled: CPCRA enrolled 194 at 11 sites and ACTG enrolled 863 at 37 sites. There were 299 (28%) patients on secondary prophylaxis. Approximately 12% were African American, 17.7% were Latino/a, and 12.4% were injection drug users. Over 70% were receiving PCP prophylaxis at baseline: 51.7% on dapsone, 19.7% on AP and 4.8% on other regimens. The median CD4 count was 60, 31.6% had a prior OI (other than PCP), and 16.1% had a positive toxoplasmosis serology.

With a median follow-up of 24 months (range 1 to 30) and 1,742 person years, the results below are as follows:

* Rates per 100 person years
** Toxo Ab+: 87 on ATQ, 83 on DAP

(El-Sadr 1997b)

* Rates per 100 person years (El-Sadr 1997b)

Adverse events necessitating discontinuation of randomized study drug were differed in both groups. Eighty-six patients in the dapsone group had to discontinue drug as compared to 46 patients in the atovaquone because of hypersensitivity (rash, fever, allergic reaction) (p<0.01), and anemia was more common in the dapsone group (11 patients) as compared to the atovaquone group ( zero patients; p<0.01). Upper GI toxicity was more prevalent in the atovaquone group (40 patients) as compared to the dapsone group (seven patients; p<0.01), and diarrhea was more prevalent in the atovaquone group (16 patients) as compared to the dapsone group (one patient; p=0.01). For those NOT on dapsone at entry, 27.5% of atovaquone patients at 24 months discontinue their assigned study drug due to intolerance as compared to 48.6% for those assigned to dapsone (p<0.01).

Discontinuing assigned study drug at patients' request (not intolerance) was more common in the atovaquone group: 104 atovaquone patients versus 52 dapsone patients (p<0.01). For those on and not on dapsone at baseline, the relative risks for discontinuation due to the patient's preference comparing atovaquone to dapsone were 1.99 (p=0.003) and 1.88 (p=0.01), respectively.

El-Sadr and colleagues' recommendation based on their CPCRA 034/ACTG 277 data reads, "Although atovaquone and dapsone are equally efficient in preventing PCP, for patients who develop intolerance to TMP/SMX and who have not received dapsone, atovaquone is the preferential initial choice based on tolerance."

Chan and colleagues tested two doses of atovaquone suspension vs. AP in Glaxo Wellcome (GW) study 213, a Phase III PCP prophylaxis trial. In GW 213, 476 HIV-positive patients with history of PCP or a CD4 count less than 200 were randomized to receive atovaquone suspension at 750 mg daily (low-dose, LDA), 1500 mg daily (high-dose, HDA), or AP at 300 mg monthly. After a median duration of one year follow-up, no significant differences were documented in either PCP occurrence or death (Chan 1997).

(Chan 1997)

ACTG 081: TMP/SMX versus AP versus Dapsone for Primary PCP Prophylaxis
ACTG 081 enrolled 843 patients with CD4 counts below200 who were given AZT and were randomized to receive TMP/SMX, AP or dapsone for primary PCP prophylaxis. A secondary comparison involved systemic and local prophylaxis; patients experiencing toxicity on TMP/SMX were first switched to the other systemic drug and only after developing an additional toxicity, to AP, while AP patients were switched first to TMP/SMX and then to dapsone for toxicity. At the end of 39 months, no significant differences were found with regard to rates of PCP, toxoplasmosis, or mortality by intent-to-treat; however, patients entering with CD4 counts below 100 who were able to tolerate systemic prophylaxis had a lower PCP rate by on-treatment analysis. The estimated 36-month cumulative risks of PCP were 18% on TMP/SMX, 17% on dapsone and 21% on AP (Bozzette 1995).

(Bozzette 1995)

While dose reductions were allowed, the dose of 2 double-strength TMP/SMX tablets daily used in ACTG 081 seems excessively high and may have caused of the high rate of switching that undoubtably led to more PCP breakthroughs. Two contemporaneous studies demonstrated TMP/SMX's efficacy at half the dose use in ACTG 081 (Hardy 1992; Schneider 1992).

The on-treatment analysis of the TMP/SMX in ACTG 081 was impressive, with a rate of PCP for those able to stay on TMP/SMX of approximately 1.5%. Nevertheless, only 21% of those randomized to TMP/SMX completed assigned study drug, as compared to 25% of the dapsone patients and 88% of the AP patients. Approximately 20% of the systemic therapy group switched twice and ended the study on AP. According to Bozzette and colleagues, because of this switching, "More patients were receiving less adequate treatments even as their vulnerability to P. carinii increased", because, as one might expect, "CD4 lymphocyte counts were much lower at the time of treatment failure than at study entry" (Bozzette 1995).

AP was also noted to be less effective than systemic therapy in patients who entered the study with CD4 counts under 100, in whom the estimated 36-month cumulative risk of reported PCP was 19% for the TMP/SMX group, 22% for the dapsone group, and 33% for the AP group (p=0.04). While ACTG 081 found no overall drastic differences, it confirmed the efficacy of all three drugs and demonstrated that the rate of PCP could drop from over 50% to as low as 17% in extremely immunosuppressed individuals during an early, primitive period of antiretroviral therapy. The fact that only 1% of all deaths in this study were attributed to PCP speaks to years of hard work on fine-tuning prophylaxis and effective treatment regimens.

The safety and efficacy of PCP prophylaxis for all patients with fewer than 200 CD4 cells makes it one of the few therapeutic certainties in HIV disease. However, as immune deterioration continues, the rate of prophylaxis failure increases. Saah and colleagues defined predictors of PCP prophylaxis failure among 476 men from the MACS:

(Saah 1995)

In this study, 76% of prophylaxis failures occurred with CD4 counts below 50, and 86% below 75.

Desensitization & Gradual Initiation of TMP/SMX
TMP/SMX is the most efficacious and cost effective PCP prophylaxis available. Nevertheless, the adverse reactions -- most commonly fever and rash -- prevent 27% to 50% of HIV-positive individuals from either fully initiating or remaining on TMP/SMX (Hardy 1992; Bozzette 1995). The onset of rash and fever is believed to be an allergic reaction involving an activation of mast cells via an immunoglobulin E (IgE) mechanism (Gruchalla 1991). Other explanations for this hypersensitivity include acetylation phenotype (Rieder 1991) and toxic hydroxylamine sulfonamide metabolite accumulation which diminish stores of glutathione (Cribb 1990). Most of these explanations only pertain to sulfamethoxazole; the role of trimethoprim here remains unclear.

The process of re-challenging patients to TMP/SMX after they have exhibited hypersensitivity has been successful and is recommended by the PHS (Carr 1993; USPHS 1997). Desensitizing patients with a history of hypersensitivity has been successful (Conant 1992). Desensitization is done by starting patients on very low doses of TMP/SMX and progressively increasing to full-dose over a course of several days or weeks (Hardy 1995).

ACTG 268 was a randomized, double-blind, Phase IV study initiated to determine if the gradual initiation of TMP/SMX could lower the incidence of rash and fever seen with routine dosing of TMP/SMX. The gradual initiation of the pediatric TMP/SMX liquid suspension was used in a step-wise fashion for 14 days. Patient were randomized to one of two schemes:

1. One, two, five, ten and twenty milliliters of TMP/SMX oral suspension for three days each until the two-week clinic visit, and one dummy pill daily, versus
2. One double strength TMP/SMX pill daily plus placebo suspension

After two weeks, all patients received the TMP/SMX double-strength pill. The primary endpoint of ACTG 268 was the development of treatment-limiting adverse effects. The median CD4 count of the 278 patients enrolled was 169. 20% of patients had a CD4 count lower than 100, 43% had between 100 and 200 CD4 cells, and 35% had a CD4 count above 200.

The results from ACTG 268 revealed that gradual initiation of TMP/SMX was better tolerated than routine initiation. The gradual initiation arm had fewer treatment-limiting adverse reactions during the first 12 weeks (p<0.001). More patients quit in the routine arm due to the severity of grade I and II pruritus (itching), rash and fever. Likewise, gradual initiation patients with less than 100 CD4 cells fared approximately two-times better (fewer endpoints/less toxicity) than those on the routine arm (p=0.02) (Para 1997).

Daily Versus Thrice Weekly TMP/SMX
In the early 1990s, administering TMP/SMX thrice-weekly was shown to be effective in various studies and is believed to help patients tolerate TMP/SMX better over routine, daily dosing (MacGregor 1992; Podzamczer 1993). The Community Program for Clinical Research on AIDS (CPCRA) recently completed study 006, a very large 2,625 patient randomized study of daily vs. thrice-weekly TMP/SMX. There were 2,212 patients on primary prophylaxis and 413 on secondary prophylaxis (El-Sadr 1997a).

The overall rates of PCP were similar in the two treatment group: 3.5% (90 cases) and 4.1% (105 case) per person-years in the daily and thrice weekly TMP/SMX groups, respectively (p=0.82). For primary and secondary prophylaxis subgroup, the relative risk (RR) for death in daily/thrice weekly TMP/SMX was 0.96 (p=0.55) and 0.70 (p=0.01), respectively. The RR for adverse events requiring discontinuation of study drug was 1.44 (p=0.01) and 0.93 (0.80) for the same groups, respectively. Because of trends favoring daily TMP/SMX for all major endpoints, the CPCRA 006 team recommended daily TMP/SMX be the preferred dose scheduling, especially for secondary prophylaxis patients.

MAC Prophylaxis Augments PCP Prophylaxis
A sub-study of California Collaborative Treatment Group (CCTG) MAC prophylaxis trial, Dunne and colleagues indicated that azithromycin helped decrease the incidence of PCP in those on PCP prophylaxis. 95% of the study population was on PCP prophylaxis (58% on TMP/SMX; 18% on dapsone; 19% on AP).

(Dunne 1996)

This sub-study indicates the multiple prophylaxis power of the macrolides. Since most PCP breakthroughs happened when patients' CD4 counts dropped below 75, this increases the rationale for initiating MAC prophylaxis at that time. Similar data revealing clarithromycin's additive effect on PCP prophylaxis was observed in the Abbott MAC prophylaxis study (Pierce 1996; Abbott, data on file; William Powderly, personal communication).

Should Patients Ever Discontinue PCP Prophylaxis?
With the advent of protease inhibitors in combination with nucleoside analogs, many patients with severely depressed immune systems are seeing drastic reductions in the their HIV viral load and marked increases in their CD4 counts. When patients have an increase in their CD4 counts above 200, some primary care physicians and HMO clinicians are discontinuing prophylaxis. The USPHS/IDSA OI prophylaxis guidelines panel recommends "continuing prophylaxis based on the nadir (the lowest) of a patient's CD4 count." (USPHS 1997)

To help in this debate, the ACTG has opened ACTG 888 (a substudy of ACTG 362) which will assess the impact of discontinuing primary PCP prophylaxis in patients whose CD4 counts have increased to over 200 cells. Patients whose CD4 cell count falls back to below 200 on two separate occasions and those with symptoms of oral thrush or unexplained fever for greater than two weeks will restart conventional PCP prophylaxis and be discontinued from the PCP substudy.

Preliminary results from a similar study were recently presented at the 37th ICAAC by Schneider and colleagues from the Netherlands. Data were presented on 45 patients who discontinued their primary PCP prophylaxis and five who stopped their secondary prophylaxis (Schneider 1997). At the time of discontinuation, the mean CD4 cell count was 370; HIV RNA was undetectable in 40 patients. The remaining ten patients' HIV RNA levels did not exceed 15,000 copies/mL. The mean CD4 cell count nadir of the patients was 77, and 11 of the 50 patients were antiretroviral naive when they started PPICT. After a median follow-up of 3.9 months (range 0.4-30.5 months; median follow-up for the five secondary prophylaxis patients, 1.3 months), no episodes of PCP were noted. It is hard to make much of these results with such short follow-up. Likewise, only having data on five secondary prophylaxis patients tells us nothing about the wisdom of stopping maintenance.

Taking a patient off prophylaxis just because of cost (Bactrim is less than 25 cents a day) or convenience is presently not recommended nor acceptable patient management. Until we have more answers, all physicians treating PWAs should follow the USPHS/IDSA OI prophylaxis guidelines.

*

Atzori C, Lu JJ, Jiang B, et al.: Diagnosis of Pneumocystis carinii pneumonia in AIDS patients by using polymerase chain reaction on serum specimens. J Infect Dis 172:1623-26, 1995.
Bacellar H, Munoz A, Hoover DR, et al.: Incidence of clinical AIDS conditions in a cohort of homosexual men with CD4+ cell counts <100/mm3. J Infect Dis 170:1284-87, 1994.
Benson C, et al.: Combined APACHE II score and serum lactate dehydrogenase as predictors off in-hospital mortality caused by first episode Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. AM Rev Resir Dis 114:319-23, 1991.
Black JR, Feinberg J, Murphy RLL, et al.: Clindamycin and primaquine therapy for mild-to-moderate episodes of Pneumocystis carinii pneumonia in patients with AIDS: AIDS Clinical Trials Group 044. Clin Infect Dis 18:905-13, 1994.
Blum RN, Miller LA, Gaggini LC, et al.: Comparative trial of dapsone versus trimethoprim/sulfamethoxazole for primary prophylaxis of Pneumocystis carinii pneumonia. J Acquir Immune Defic Syndr 5:341-47, 1992.
Bozzette SA, et al.: A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 323:1451-57, 1990.
Bozzette SA, Finkelstein DM, Spector SA, et al.: A randomized trial of three anti-Pneumocystis agents in patients with advanced human immunodeficiency virus infection. N Engl J Med 332:693-99, 1995.
Brenner M, Ognibene FP, Lack EE, et al.: Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia. Am Rev Respir Dis 136:1199-206, 1987.
CDC: Guidelines for preventing the transmission of tuberculosis in health-care setting with special focus on HIV-related issues. MMWR 39:1-29, 1990.
CDC: Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with HIV. MMWR 41:1-12, 1992.
Carr A, Penny R, Cooper DA: Efficacy and safety of rechallenge with low-dose trimethoprim-sulfamethoxazole in previously hypersensitive HIV-infected patients. AIDS 7:65-71, 1993.
Chaisson RE: The natural history of opportunistic infections in patients with AIDS [abstract: S026]. 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, 1996.
Chan C, Montaner J, Lefebvre E, et al.: Prophylaxis of Pneumocystis carinii pneumonia - comparison of Mepron suspension with aerosolized pentamidine [abstract: 290]. 35th IDSA Meeting, Toronto, 1997.
Conant M, Dybul M: Trimethoprim/sulfamethoxazole hypersensitivity and desensitization in HIV disease [abstract: Po.B.3291]. VIII Intl Conf AIDS, Florence, 1992.
Contini C, Cultera R, Merolla R, et al.: PCP for detection of Pneumocystis carinii in blood cells [letter]. J Clin Microbiol 33:1431-2, 1995.
Cribb AE, Speilberg SP: Hepatic microsomal metabolites of sulfamethoxazole to the hydroxylamine. Drug Meta Dispos 18:784-87, 1990.
Currier JS, Williams, and the ACTG 320 Team: Preliminary ACTG 320 OI data analysis [presentation]. 23rd AIDS Clinical Trials Group Meeting, Washington, D.C., July 19-23, 1997.
Dohn M, Weinberg W, Torres RA, et al.: Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med 121:174-80, 1994.
Dohn MN, Frame P: Protozoan Infections. In: Powderly WG ed. Manual of HIV Therapeutics. Philadelphia:Lippincott:Raven. In preparation. To be published 1997.
Dunne MW, Havlir D, Dube M, et al.: Prevention of Pneumocystis carinii pneumonia with azithromycin [abstract: Tu.B. 410]. XI Intl Conf AIDS, Vancouver , 1996.
Edman JC, Kovacs JA, Masur H, et al.: Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi. Nature 334:519-22, 1988.
Efferen LS, Nadarajah D, Palat DS: Survival following mechanical ventilation for Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome: a different perspective. Am J Med 87:401-04, 1989.
El-Sadr W, Luskin-Hawk L, Pulling C, et al.: Daily versus thrice weekly trimethoprim-sulfamethoxazole (TMP/SMX) in the prevention of Pneumocystis carinii pneumonia (PCP) [abstract: I-146]. 37th ICAAC, Toronto, 1997.
El-Sadr W, Murphy R, Luskin-Hawk R, et al.: A randomized, controlled study of daily dapsone and daily atovaquone for prophylaxis against PCP in HIV-infected patients who are intolerant of trimethoprim and/or sulfamethoxazole: CPCRA 034/ACTG 277 [Executive Summary]. CPCRA/ACTG, DAIDS, NIAID, NIH, 1997.
Falloon J, et al.: The pharmacokinetics of atovaquone suspension in patients with HIV infection [abstract: 242]. First International Conference on Human Retroviruses and Related infections, Washington, DC, 1993.
Fischl MA, Dickinson GM, LaVoie L: Safety and efficacy of sulfamethoxazole and trimethoprim chemoprophylaxis for Pneumocystis carinii pneumonia. JAMA 259:1185-89, 1998.
Friedman Y, Franklin C, Rackow EC, et al.: Improved survival in patients with AIDS, Pneumocystis carinii pneumonia, and severe respiratory failure. Chest 96:862-66, 1989.
Garay SM, Greene J: Prognostic indicators of the initial presentation of Pneumocystis carinii pneumonia. Chest 95:769-72, 1989.
Girard PM, Landsman R, Gaudebout C, et al.: Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. N Engl J Med 328:1514-20, 1993.
Gruchalla R, Sullivan TJ: Detection of human IgE to sulfamethoxazole by skin testing with sulfamethoxazole-poly-L-tyrosine. J Allergy Clin Immunol 88:784-92, 1991.
Hardy WD, Feinberg J, Finkelstein DM, et al.: A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients acquired immunodeficiency syndrome. N Engl J Med 327:1842-8, 1992..
Hardy WD: Treatment and prevention of PCP and multiple opportunistic pathogen prophylaxis strategies. Improving the Management of HIV Disease (International AIDS Society) 3(4):20-24, 1995.
Hirschel B, Lazzarin A, Choppard P, et al.: A controlled trial of inhaled pentamidine for primary prevention pf Pneumocystis carinii pneumonia. N Engl J Med 324:1079-83, 1991.
Hoover DR, Saah AJ, Bacillar H, et al.: Clinical manifestations of AIDS in the era of Pneumocystis prophylaxis. N Engl J Med 329:1922-26, 1993.
Huang L, Hecht FM, Stansell JD, et al.: Suspected Pneumocystis carinii pneumonia with a negative induced sputum examination. Is early bronchoscopy useful? Am J Resir Crit Care Med 151:1866-71, 1995.
Huang L: Update: Pneumocystis carinii pneumonia. HIVNEWSLINE October, 1996.
Hughes W, Leoung G, Bozzette SA, et al.: Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med 328:1521-7, 1993.
Kemper CA, Tucker RM, Lang OS, et al.: Low-dose dapsone prophylaxis of Pneumocystis carinii pneumonia in AIDS and AIDS-related complex. AIDS 4:1145-48, 1990.
Klein NC, Duncanson FP, Lenox TH, et al.: Trimethoprim-sulfamethoxazole versus pentamidine for Pneumocystis carinii pneumonia in AIDS patients: results of a large prospective randomized treatment trial. AIDS 6:301-05, 1992.
Leoung GS, Mills J, Hopewell PC, et al.: Dapsone-trimethoprim for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med 105:45-48, 1986.
Leoung GS, Feigal DW, Montgomery AB, et al.: Aerosolized pentamidine for prophylaxis against Pneumocystis carinii pneumonia. The San Francisco community prophylaxis trial. N Engl J Med 323:769-75, 1990.
Limper AH, Offord KP, Smith TF, et al.: Pneumocystis carinii pneumonia. Differences in lung parasite number and inflammation in patients with and without AIDS. Am Rev Respir Dis 140:1204-09, 1989.
Limper AH: Parasitic adherence and host responses in the development of Pneumocystis carinii pneumonia. Semin Respir Infect 6:19-26, 1991.
MacGregor R, Morgan A, Graziani Al, et al.: Efficacy and tolerance of intermittent versus daily cotrimazole for PCP prophylaxis in HIV-positive patients. Am J Med 92:227-29, 1992.
Mallolas J, Zamora L, Gatell JM, et al.: Primary prophylaxis for Pneumocystis carinii pneumonia: a randomized trial comparing cotrimazole, aerosolized pentamidine and dapsone plus pyrimethamine. AIDS 7:59-64, 1993.
Masur H, Ognibene FP, Yarchoan R, et al.: CD4 counts as a predictor of opportunistic pneumonia in human immunodeficiency virus (HIV) infection. Ann Intern Med 11:223-31, 1989.
Medina I, Mills J, Leoung G, et al.: Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 323:776-82, 1990.
Michaels S, Clark R, Kissenger P: Difference in the incidence rates of opportunistic infections before and after the availability of protease inhibitors [abstract]. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, 1998.
Moe AA, Hardy DW: Pneumocystis carinii pneumonia in the HIV-seropositive patient. Infect Dis Clin North Am 8:331-64, 1994.
Montaner JSG, et al.: Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrom Ann Intern Med 113:14-20, 1990.
Para MF, Dohn M, Frame P, et al.: ACTG 286 trial: gradual initiation of trimethoprim/sulfamethoxazole as a primary prophylaxis for Pneumocystis carinii pneumonia [abstract: 4]. 4th Conference on Retroviruses and opportunistic Infections, Washington, DC, 1997.
Phair J, Munoz A, Detels R, et al.: The risk of developing Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. Multicenter AIDS Cohort Study Group. N Engl J Med 322:161-65, 1990.
Pierce M, Crampton S, Henry D, et al.: A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced acquired immunodeficiency syndrome. N Engl J Med 335:384-91, 1996.
Podzamczer D, Satin M, Jimenez J, et al.: Thrice-weekly cotrimazole is better than weekly dapsone-pyrimethamine for the primary prevention of Pneumocystis carinii pneumonia in HIV-infected patients. AIDS 7:501-06, 1993.
Rieder MJ, Shear NH, Kanee AS, et al.: Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions. Clin Pharmacol Ther 49:13-17, 1991.
Saah AL, Hoover DR, Peng Y, et al.: Predictors for failure of Pneumocystis carinii pneumonia prophylaxis. Multicenter AIDS Cohort Study. JAMA 237:1197-202, 1995.
Safrin S, Finkelstein DM, Feinberg J, et al.: Comparison of three regimens for the treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med 124:792-802, 1996.
Sattler FR, Cowan R, Neilsen DM, et al.: Trimethoprim-sulfamethoxazole compared with pentamidine for the treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med 109:280-87, 1988.
Sattler FR, Frame P, Davis R, et al.: Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031. J Infect Dis 170:165-72, 1994.
Schneider MM, Hoepelman AI, Eeftinck Schattenkerk JK, et al.: A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with acquired immunodeficiency virus infection. N Engl J Med 327:1836-41, 1992.
Schneider, MME, Borleffs JCC, Jaspers CAJJ, Hoepelman IM: Discontinuation of Pneumocystis carinii pneumonia (PCP) prophylaxis in HIV-infected patients with an increase of their CD4 cell counts (>200/mm3), due to aggressive antiretroviral therapy [abstract: LB69]. 37th ICAAC, Toronto, 1997.
Schwarcz S, Katz M, Hirozawa A, et al.: Prevention of Pneumocystis carinii pneumonia: who is not receiving recommended prophylaxis? [abstract: I17]. 35th ICAAC, San Francisco, 1995.
Selik RM, Chu SY, Ward JW, et al.: Trends in infectious diseases and cancers among persons dying of HIV infection in the United States from 1987 to 1992. Ann Intern Med 123:933-36, 1995.
Slavin MA, Hoy JF, Stewart K, et al.: Oral dapsone versus nebulizer pentamidine for Pneumocystis carinii pneumonia prophylaxis: an open randomized prospective trial to assess efficacy and hematological toxicity. AIDS 10:1169-74, 1992.
Stover DE, White DA, Romano PA, et al.: Diagnosis of pulmonary disease in acquired immune deficiency syndrome (AIDS). Role of bronchoscopy and bronchoalveolar lavage. Am Rev Respir Dis 130:659-62, 1984
Stringer SL, Stringer JR, Blase MA, et al.: Pneumocystis carinii: sequence from ribosomal RNA implies a close relationship with fungi. Exp Parasitol 68:450-61, 1989.
Toma E, Fournier S, Dumont M, et al.: Clindamycin/primaquine versus trimethoprim-sulfamethoxazole as primary therapy for Pneumocystis carinii pneumonia in AIDS: a randomized, double-blind pilot trial. Clin Infect Dis 17:178-84, 1993.
USPHS: Consensus statement of the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 323:1500-04, 1990.
USPHS/Infectious Disease Society of America. Guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR 46(RR-12): 12-13, 1997.
Ward JW, Hanson DL, Chu Sy, et al.: Survival and trends in anti-retroviral therapy and antimicrobial prophylaxis among persons with 1993-defined AIDS [abstract: I86]. 35th ICAAC, San Francisco, 1995.
Watcher RM, et al.: Pneumocystis carinii pneumonia and respiratory failure in AIDS. Am Rev Repir Dis 143:251-56, 1991.
Wharton JM, Coleman DL, Wofsy CB, et al.: Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective randomized trial. Ann Intern Med 105:37-44, 1986.

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