AIDS INFORMATION NEWSLETTER Michael Howe, MSLS, Editor AIDS Information Center VA Medical Center, San Francisco (415) 221-4810 ext 3305 December 29, 1995 Opportunistic Infections (Part XVI) Pneumocystis carinii Pneumonia (PCP) [Oportunistic Infections and Related Disorders; From AmFAR's AIDS/HIV Treatment Directory, Vol. 7, No. 4 (January 1995)] PATHOGEN: Pneumocystis carinii has generally been classified as a protozoan parasite; some studies indicate it may be a fungus, with which it shares certain genetic sequences. SITES OF INFECTION: Usually the lungs. Rarely, in extrapulmonary sites, including the lymph nodes, bone marrow, spleen, and liver. SYMPTOMS: Fever; dry, nonproductive cough; chest tightness; difficulty breathing. DIAGNOSIS: By microscopic examination of induced sputum, bronchoalveolar lavage, transbronchial or open lung biopsy. TREATMENT RESULTS: TMP/SMX and IV pentamidine are standard treatments for acute PCP. TMP/SMX is generally preferred over pentamidine because of its safety profile. Trimetrexate with concurrent leucovorin is approved for the treatment of moderate-to-severe PCP in patients intolerant to TMP/SMX, and atovaquone (formerly 566) is approved for mild-to-moderate PCP in patients intolerant to TMP/SMX. Hughes et al. compared atovaquone (750 mg tid) and TMP/SMX (320 mg/1600 mg tid) for the treatment of mild to moderately severe PCP. Therapy was successful in 99/160 (62%) patients randomized to atovaquone and 103/162 (64%) patients randomized to TMP/SMX. More patients in the atovaquone group failed due to lack of response, while more patients in the TMP/SMX group failed due to drug toxicity (20% of atovaquone recipients and 7% of TMP/SMX recipients discontinued due to inadequate response, while 7% of atovaquone recipients and 20% of TMP/SMX recipients discontinued due to drug toxicity). Toxicities included rash, liver function abnormalities, vomiting and fever. Mortality within four weeks of the completion of treatment was higher in the atovaquone group (11 patients) than in the TMP/SMX group (1 patient) (P = 0.003). Dohn et al. compared atovaquone 750 mg tid PO to pentamidine 3-4 mg/kg/day IV as primary therapy in patients with mild or moderate PCP. Successful therapy was achieved in 32/56 (57%) and 21/53 (40%) of patients randomized to atovaquone and pentamidine, respectively (P = 0.085). Lack of response was observed in 15/56 (29%) and 10/53 (19%) of atovaquone and pentamidine recipients, respectively (P = .176). Adverse events requiring discontinuation of therapy occurred in 5/56 (7%) and 29/53 (55%) of atovaquone and pentamidine recipients, respectively (P < .001). Seven patients in the atovaquone group and 13 in the pentamidine group died within the first four weeks (P = .529). Sattler et al. reported results from a multicenter study (ACTG 029/031) comparing trimetrexate (TMTX) with concurrent leucovorin to TMP/SMX as first-line tretment for acute moderately severe PCP in 215 patients. The cumulative incidence of serious and treatment- terminating adverse events including hematologic toxicities was less with trimetrexate (P<.001). Although the response rates were similar for both drugs, survival was greater in the TMP/SMX arm (mortality was 12% in the TMP/SMX group and 20% in the TMTX group (P=.028). The investigators concluded that TMP/SMX is a superiod first-line therapy for moderately severe PCP. ACTG 039 investigated trimetrexate in patients who did not respond to or were intolerant of TMP/SMX and IV pentamidine. 84/159 (53%) patients intolerant to both standard therapies and 48/160 (30%) patients either unresponsive to both or unresponsive to one and intolerant of the other tolerated at least 14 days of treatment and survived at least one month. Investigators concluded that trimetrexate is a useful and well-tolerated salvage therapy. Feinberg et al. evaluated the results of an expanded-access program which provided trimetrexate to 752 patients unable to take TMP/SMX and IV pentamidine. 34% of patients were classified as responders. Leoung et al. treated 15 patients for a first episode of mild to moderate PCP with trimethoprim (20 mg/kg PO qd x21d) and dapsone (100 mg PO qd x21 d). All improved within 3-10 days. Side effects (nausea, vomiting, rash) occurred in 14/15, with treatment discontinued in 2/15 (severe rash). Medina et al. randomized 60 patients with AIDS and mild to moderately-severe PCP to receive either TMP/dapsone (20 mg/day and 100 mg/day PO respectively) or TMP/SMX (20 mg/kg/day and 100 mg/kg/day PO respectively). No patients received concomitant AZT. The regimens were equally effective, with 2/30 patients in the TMP/dapsone group failing, and 3/30 in the TMP/SMX group failing. TMP/SMX was associated with significantly greater toxicity: 9/30 patients who received TMP/dapsone and 17/30 who received TMP/SMX had a major adverse reaction requiring a switch to IV pentamidine. The most frequent toxicity in the TMP/dapsone group was rash; in the TMP/SMX group elevated LFTs, neutropenia, and rash were most frequently observed. Rohde et al. studied 15 patients with mild to moderate PCP who had been treated with clindamycin/primaquine (900 mg qid/30 mg qd x 21d), matching them retrospectively with patients receiving TMP/SMX. In both groups steroids were added on a declining dose if arterial oxygen pressure was below 70 mmHg. All patients showed clinical improvement. Response rates were similar in both groups. Relapse occurred in three patients in the TMP/SMX group and in one patient in the clindamycin/primaquine group. In general, side effects of TMP/SMX were more severe and included marrow suppression, rashes, elevated liver enzymes, and GI distress; clindamycin/primaquine was associated with methemoglobinemia. Montgomery B et al. enrolled 379 patients with PCP and a pO2 less than 55 mmHg in a randomized, double-blind trial comparing TMP/SMX to aerosol pentamidine (AP) for treatment of acute PCP. AP was associated with a slower clinical response and more relapses than TMP/SMX, while TMP/SMX was associated with more adverse reactions (rash, elevated liver-enzyme levels, fever, neutropenia, and nausea). Investigators also noted that the risk of pneumothorax and extrapulmonary PCP appears to be greater with AP than with TMP/SMX. Waskin et al. found that the incidence of transient diabetes among PCP patients was 22% with IV pentamidine and 6% among long-term users of aerosolized pentamidine for PCP prophylaxis. Adjunctive corticosteroid administration (added to TMP/SMX or pentamidine IV), when initiated at the beginning of treatment, decreases the potentially life-threatening inflammatory response and respiratory distress associated with moderate to severe PCP. A consensus conference convened by the NIAID to review the results of five separate studies determined that early adjunctive steroid therapy reduces the likelihood of death, respiratory failure and deterioration in moderate to severe PCP when adjunctive therapy is initiated as early as possible; no benefit has been proven in milder forms of PCP. Adjunctive corticosteroids are now standard therapy for moderate or severe PCP, as defined by a room air PO2 less than 70 mmHg. The long-term benefit of adjunctive use of corticosteroids has not been established. Adjunctive corticosteroid treatment has not been shown to reactivate tuberculosis or fungal diseases with measurable frequency. A non-randomized retrospective chart review found that corticosteroid use was associated with a reduced incidence of adverse skin reactions to TMP/SMX in AIDS patients receiving treatment for acute PCP (Caumes et al.). 38 patients in the review received TMP/SMX alone, and 23 received TMP/SMX plus corticosteroids for hypoxemia. Rashes occurred in 18/38 (47%) patients receiving TMP/SMX alone and 3/23 (13%) receiving TMP/SMX & corticosteroids. A higher rate of mucocutaneous herpes simplex infections was observed in the patients receiving corticosteroids (P = 0.012). PROPHYLAXIS RESULTS, ADULTS: TMP/SMX (Bactrim, Septra) is the treatment of choice for the prevention of PCP. The U.S. Public Health Service Task Force on PCP prophylaxis recommends TMP/SMX (one double-strength tablet every day) for both primary and secondary prophylaxis of PCP in HIV-infected patients with no history of severe reactions to TMP/SMX, and either prior PCP, a CD4 count below 200/mm3, or unexplained fever or thrush (CDC, 1992). Bozzette and co-workers presented preliminary results from a trial (ACTG 081) comparing three regimens for the primary prophylaxis of PCP. 842 patients with CD4 counts <200/mm3 and no prior history of PCP were randomized to receive TMP/SMX (one double-strength tablet daily), aerosol pentamidine (300 mg monthly), or dapsone (50 mg twice daily). The median follow-up was 39 months. Upon intent-to-treat analysis, PCP occurred with equal frequency in the three groups. Forty-two, 54 and 48 cases of PCP occurred in the TMP/SMX, aerosol pentamidine, and dapsone groups, respectively (P = 0.22). Survival was equivalent in the three groups (134, 131, and 138 deaths). Fewer side effects requiring a switch in treatment assignment occurred in the aerosol pentamidine group (P < 0.001 ). The mean time to discontinuation of assigned treatment was 14.6, 17.1, and 13.7 months in the TMP/SMX, aerosol pentamidine, and dapsone groups respectively. Rizzardi et al. randomized 220 patients to receive TMP/SMX (one double-strength tablet daily) or aerosolized pentamidine (300 mg monthly). After two years follow-up, intent-to-treat analysis showed that 6 and 5 patients developed PCP and 30 and 18 patients died in the TMP/SMX and pentamidine groups respectively (differences not significant). The relative risk of mortality at two years was 1.2 in the pentamidine group compared with the TMP/SMX group (95% confidence interval 0.33 - 4.37). Schneider et al. randomized 213 HIV+ patients with CD4 counts <200/mm3 and no history of PCP to receive one of two regimens of TMP/SMX (one single strength or double strength tablet daily) or aerosolized pentamidine (300 mg monthly via Respirgard II nebulizer). After a mean followup of 264 days, 6/71 pentamidine recipients had a confirmed episode of PCP, while no patient in either TMP/SMX group had PCP (P = 0.002). Adverse reactions requiring treatment discontinuation were higher in both TMP/SMX groups (17/71 on 480 mg/day and 18/71 on 960 mg/day) compared to the aerosolized pentamidine group (2/71). Adverse effects occurred earlier in the higher-dose TMP/SMX group than in the lower-dose TMP/SMX group. Hardy et al. randomized 310 AIDS patients who had recovered from one bout of PCP to receive either one double-strength TMP/SMX tablet a day or aerosolized pentamidine 300 mg delivered by a Respirgard II nebulizer every 4 weeks (ACTG 021). All patients received zidovudine. After a mean followup of 17.4 months, PCP had recurred in 14/154 (9%) patients randomized to TMP/SMX and 36/156 (23%) patients randomized to aerosolized pentamidine. Adverse reactions requiring a change in treatment occurred in 42/154 (27%) of TMP/SMX recipients and 6/156 (4%) of aerosolized pentamidine recipients. Rash and fever accounted for most of the toxicities. There were no differences in the rates of hematologic or hepatic abnormalities between the two groups. Survival was equivalent in the two groups. Borleffs et al. randomized 230 patients with CD4 <200/mm3 and no previous PCP to receive aerosolized pentamidine (300 mg once monthly) or one of two doses of TMP/SMX (one single-strength or double-strength tablet daily). After 9 months' follow-up, an interim analysis showed that 11% of AP recipients and no TMP/SMX recipients had developed PCP. Adverse reactions requiring a switch in treatment occurred in 2% of the AP group, 17% of the low-dose TMP/SMX group and 18% of the high-dose TMP/SMX group. Several studies suggest that TMP/SMX (one double strength tablet) delivered three times a week (as opposed to daily) is effective as primary prophylaxis for PCP with reduced incidence of adverse reactions. Ruskin et al. conducted a retrospective analysis of TMP/SMX three times weekly as PCP prophylaxis in 116 patients (71 had a prior history of active PCP, mean follow-up 18.5 months; 45 never had PCP, but CD4 below 200/mm3; mean follow-up 24.2 months). None of 116 patients developed PCP; 28% had side effects (rash, pruritus, nausea); 15/116 discontinued treatment, with 11/15 clearly drug intolerant. Aerosolized pentamidine, administered by the Respirgard II nebulizer, is approved for the primary prophylaxis of PCP in HIV-infected patients with less than 200 CD4+ cells/mm3 and as secondary prophylaxis. The U.S. Public Health Service Task Force on PCP prophylaxis recommends aerosol pentamidine as primary or secondary prophylaxis in patients who cannot tolerate TMP/SMX. The Task Force recommends either the Respirgard II nebulizer (300 mg/month) or the Fisons nebulizer (five 60 mg loading doses over a two-week period, followed by 60 mg every 2 weeks). Common side effects include cough and bronchospasm; less common side effects include pneumothorax and transient diabetes. AP is not effective in preventing extrapulmonary PCP. Several studies have established the efficacy of aerosolized pentamidine delivered through the Fisons hand-held nebulizer (Fisoneb). Montaner et al. enrolled 162 post-PCP AIDS patients in a double-blind placebo-controlled study of aerosolized pentamidine 60 mg every two weeks administered through the Fisons nebulizer. After a mean follow-up of 15.2 weeks, 27/ 78 placebo recipients and 5/84 pentamidine recipients had PCP relapses (P< 0.001). Mild to moderate adverse reactions in 15/78 placebo recipients and 28/84 pentamidine recipients (cough and bronchospasm were most frequent). Murphy et al. enrolled 175 post-PCP patients in a blinded dose-comparison study of aerosolized pentamidine 5, 60, or 120 mg every two weeks administered through the Fisons nebulizer. While the low-dose regimen was ineffective, the 60 and 120 mg regimens were equally effective. At 52 weeks, probability of being PCP-free was 88% in the 60 mg group and 93% in the 120 mg group. A study directly comparing the Fisons and Respirgard II nebulizers has not been conducted. Blum et al. prospectively compared dapsone (100 mg/day) and TMP/SMX (one double-strength tablet/day) as primary prophylaxis for PCP in HIV-positive patients with CD4+ counts below 200/mm3. After 1,638 patient months of followup, 1/47 patients randomized to dapsone and 1/39 patients randomized to TMP/SMX developed PCP. 33/47 dapsone recipients and 25/39 TMP/SMX recipients discontinued their study therapy, most frequently for rash. Ten patients switched from dapsone to TMP/SMX, 4 successfully; and 11 patients crossed over from TMP/SMX to dapsone, 6 successfully. Slavin et al. conducted a randomized comparison of dapsone (100 mg PO twice weekly) and aerosolized pentamidine (400 mg nebulized monthly) for PCP prophylaxis in patients with CD4 counts below 200/mm3 or a previous episode of PCP. 37/50 dapsone recipients and 32/46 AP recipients had a previous episode of PCP. Mean CD4 counts at entry were 128/mm3 and 124/mm3 in the dapsone and AP groups, respectively. All patients received AZT. After a median followup of 18 months, 9/50 dapsone recipients and 8/46 AP recipients had developed PCP (no difference). The rates of adverse reactions were equal in the two groups (4 rash and 2 nausea on dapsone, and 5 cough and 1 dizziness on AP). Opravil et al. randomized 528 patients to receive either dapsone/pyrimethamine (200 mg/75 mg once weekly) or aerosolized pentamidine (300 mg once monthly via Respirgard II nebulizer). All patients had CD4 counts below 200/mm3 at baseline and 20% had previous PCP. After 335 days' mean followup, intent-to-treat analysis showed that 12/291 dapsone/pyrimethamine recipients and 13/242 AP recipients had developed PCP (no significant difference). Intolerance requiring a switch in treatment occurred in 30% of dapsone/pyrimethamine recipients and 4% of AP recipients. Most frequent side effects were nausea, fever, and hematologic toxicity. Girard et al. randomized 349 symptomatic patients with CD4 counts below 200/mm3 to receive dapsone/pyrimethamine (50 mg daily/50 mg weekly) or aerosolized pentamidine (300 mg monthly) on an open-label basis. After a median follow-up of 539 days, 10/173 dapsone/pyrimethamine recipients and 10/176 aerosolized pentamidine recipients had developed PCP. 42 dapsone/pyrimethamine recipients and 3 aerosolized pentamidine recipients discontinued therapy due to toxicity. No difference in survival was observed. Two randomized studies suggest that low-dose dapsone (100 mg/week) with pyrimethamine may be less effective than other strategies for PCP prophylaxis. Antinori et al. randomized 197 patients with CD4 counts below 200/mm3 and no prior PCP to receive dapsone/pyrimethamine (100 mg weekly/25 mg twice weekly), aerosolized pentamidine (300 mg monthly via Respigard II nebulizer), or TMP/SMX (one double-strength tablet every other day). After a median follow-up of 7.7 months, PCP had developed in 9/63, 4/68 and 1/66 of dapsone/pyrimethamine, aerosolized pentamidine and TMP/SMX recipients respectively. Upon intent-to-treat analysis, the difference between the TMP/SMX and D/P groups was significant (P = 0.0008). Other comparisons did not show significant differences. Podzamczer et al. randomized 166 patients with CD4 counts below 200/mm3 to receive dapsone/ pyrimethamine (100 mg weekly/25 mg weekly) or TMP/SMX (2 double-strength tablets three times weekly). After a mean follow-up of 380 days, intent-to-treat analysis showed that PCP had developed in 13/85 (15.2%) of dapsone/ pyrimethamine recipients and 3/81 (3.7%) of TMP/SMX recipients (P = 0.01). By contrast, the results of another randomized study (Mallolas et al.) suggest that weekly dapsone/pyrimethamine may be comparable to standard therapies. 331 HIV-infected patients with CD4 counts <200/mm3 or a previous diagnosis of AIDS were randomized to receive dapsone/pyrimethamine (100/25 mg weekly), aerosolized pentamidine (300 mg monthly) or TMP/SMX (160/800 mg thrice weekly). The mean follow-up was 313 days. Upon intention-to-treat analysis, the PCP rates per year of observation were 8.3%, 5.6%, and 3.0% in the D/P, AP and TMP/SMX groups, respectively. These differences were not statistically significant. Cheung et al. conducted a retrospective review of 89 patients who received intramuscular pentamidine 300 mg or 4 mg/kg monthly as prophylaxis for PCP. 34/89 had prior PCP, the remainder had CD4+ count <210/mm3. After a median follow-up of 8 months, 3/89 patients developed PCP. Toxicities observed were two cases of hypotension, three sterile abscesses and three cases of glucose intolerance. One report described the experience of three patients who received atovaquone 750 mg three times daily as prophylaxis for PCP (Fisher et al.). The 3 patients had multiple prior bouts of PCP, other AIDS-defining OI, and very low CD4 counts. All 3 were intolerant of TMP/SMX, dapsone, and aerosolized pentamidine. None of the patients had an episode of PCP during 3, 5 and 6 months of follow-up respectively. In order to prospectively evaluate the efficacy of atovoaquone for PCP prophylaxis, a randomized, open-label study is under way which compares atovaquone oral suspension 750 mg or 1500 mg daily with aerosolized pentamidine 300 mg monthly. All patients will have CD4 counts <200/mm3, or a prior bout of PCP, or constitutional symptoms of HIV infection, and intolerance of TMP/SMX. PROPHYLAXIS RESULTS, CHILDREN: In March, 1991, the CDC released guidelines for the prophylaxis of PCP in HIV-infected children. Since young children have much higher CD4+ counts than adults, the recommendations are stratified according to age. Prophylaxis is recommended when CD4+ counts fall below 1,500/mm3 in children between one and 11 months, below 750/mm3 in children between 12 and 23 months, below 500/mm3 in children between 24 months and five years, and below 200/mm3 in children over six years old. For any child whose CD4+ percentage falls below 20%, prophylaxis is recommended regardless of age or absolute CD4+ count. Simonds et al. reported that the incidence of PCP among infants has not declined substantially since prophylaxis guidelines were published. Most recent cases can be attributed to lack of timely evaluation for HIV. Using CD4+ counts as criteria for prophylaxis may be impractical for infants because counts may be difficult to obtain before the age of peak PCP risk (3-6 mos), and may decline rapidly before PCP. The recommended regimen is TMP 150 mg/m2/d PO with SMX 750 mg/m2/day PO in divided doses tiw on consecutive days (e.g. M-Tue-W). Alternative schedules include the same dosages given as a single daily dose tiw on consecutive days; the same dosages given in two divided doses every day; and the same dosages given as two divided doses tiw on alternating days (e.g. M-W-F). In the case of intolerance to TMP/SMX, alternative regimens are aerosolized pentamidine 300 mg/month via the Respirgard II nebulizer; dapsone (for children > 1 month) 1 mg/kg/day PO; or IV pentamidine 4 mg/kg every two or four weeks. The safety of aerosol pentamidine in infants was evaluated by Hand et al. Seven infants (mean age 6.7 months) with HIV infection were given monthly treatments with aerosolized pentamidine, with the dose calculated to be equivalent to an adult dosage of 300 to 600 mg/month. The side effects observed were similar to those seen in adults, with mild coughing and wheezing being most frequent. The investigators concluded that aerosolized pentamidine is safe in this population. REFERENCES: Antinori A et al. Failure of low-dose dapsone- pyrimethamine in primary prophylaxis of Pneumocystis carinii pneumonia. Lancet (letter) 340:788, 1992. Blum RN et al. Comparative trial of dapsone versus trimethoprim/sulfamethoxazole for primary prophylaxis of Pneumocystis carinii pneumonia. J AIDS 5:341-7, 1992. Borleffs JCC et al. Pentamidine versus two doses of cotrimoxazole in primary prophylaxis of Pneumocystis carinii pneumonia in HIV-infected patients. Abstract O-8A.3, Intl Cong Drug Ther HIV Infect, Glasgow, 1992. Bozzette SA et al. Comparative 6 month tolerance for thrice weekly versus daily trimethoprim/sulfamethoxazole (T/S) with and without leucovorin for the primary prevention of HIV-related PCP. 31st ICAAC, abstract #229, 1991. Camus E et al. Effect of corticosteroids on the incidence of adverse cutaneous reactions to trimethoprim-sulfamethoxazole during treatment of AIDS-associated Pneumocystis carinii pneumonia. Clin Infect Dis 18:319-23, 1994. CDC. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with HIV. MMWR 41: 1-12, 1992. Cheung T et al. Intramuscular (IM) pentamidine for PCP prophylaxis. VII Intl Conf AIDS, Florence. Vol 2: 238(W.B.2227), 1991. Dohn M et al. Atovaquone vs. pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Abstract PO-B10-1421, IX Intl Conf AIDS, Berlin, 1993. Feinberg J et al. Trimetrexate (TMTX) salvage therapy for PCP in AIDS patients with limited therapeutic options. Abstract PoB 3297, VIII Intl Conf AIDS, Amsterdam, 1992. Fisher MJ et al. Atovaquone as prophylaxis against Pneumocystis carinii pneumonia (letter). J Inf 28:103-4, 1994. Girard PM et al. Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. NEJM 328:1514-20, 1993. Hand IL et al. Aerosolized pentamidine for prophylaxis of Pneumocystis carinii pneumonia in infants with human immunodeficiency virus infection. Pediatr Infect Dis J 13:100-4, 1994. Hardy WD et al. A controlled trial of trimethoprim- sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trials Group Protocol 021. NEJM 327: 1842-8, 1992. Hughes WT et al. Comparison of atovaquone (566C80) and trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. NEJM 328:1521-7, 1993. Leoung GS et al. Dapsone-Trimethoprim for Pneumocystis carinii Pneumonia in the Acquired Immunodeficiency Syndrome. Ann Int Med 105(1): 45-8, 1986. Mallolas J et al. Primary prophylaxis for Pneumocystis carinii pneumonia: a randomized trial comparing cotrimoxazole, aerosolized pentamidine and dapsone plus pyrimethamine. AIDS. 1993 Jan;7(1):59- 64. Medina I et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. NEJM 323:776-82, 1990. Montaner JSG et al. Aerosol pentamidine for secondary prophylaxis of AIDS-related PCP. A randomized, placebo-controlled study. Ann Int Med 114: 948-53, 1991. Montgomery AB et al. Aerosolized pentamidine vs. trimethoprim/ sulfamethoxazole for acute Pneumocystis carinii pneumonia (PCP): a randomized double-blind trial. VI Intl Conf AIDS San Francisco, 1:220(Th.B.395), 1990. Murphy RL et al. Aerosol pentamidine prophylaxis following PCP in AIDS patients: results of a blinded dose-comparison study using an ultrasonic nebulizer. Am J Med 90: 418-26 1991. Opravil M et al. Dapsone-pyrimethamine vs. aerosolized pentamidine for combined prophylaxis of PCP and toxoplasmic encephalitis. Abstract PO-B10-1429, IX Intl Conf AIDS, Berlin, 1993. Podzamczer D et al. Thrice weekly co-trimoxazole is better than weekly dapsone-pyrimethamine for the prevention of pneumocystis carinii pneumonia in HIV-infected patients. AIDS 7:501-6, 1993. Rohde I et al. Efficacy of clindamycin/primaquine vs. trimethoprim/sulfamethoxazole in acute treatment of Pneumocystis carinii pneumonia. VI Intl Conf AIDS San Francisco, 1:221 (Th.B.397), 1990. Ruskin J and LaRiviere M. Low-dose co-trimoxazole for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus disease. Lancet 337:468-71, 1991. Rizzardi GP et al. Risks and benefits of aerosolized pentamidine and cotrimoxazole in primary prophylaxis of Pneumocystis carinii pneumonina in a 2-yr randomized controlled trial. Abstract P202, 4th Euro Conf on Clin Treat of HIV Infect, Milan 1994. Sattler 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 170:165-172, 1994. Schneider MME et al. A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. NEJM 327: 1836-41, 1992. Simonds et al. The impact of prophylaxis guidelines on pneumocystis carinii pneumonia (PCP) in infants, U.S.A. Abstract #389B, X Intl Conf AIDS, Yokohama, 1994. Slavin M et al. Oral dapsone versus nebulized pentamidine for Pneumocystis carinii pneumonia prophylaxis: an open randomized prospective trial to assess efficacy and hematological toxicity. AIDS 6: 1169-74, 1992. Waskin H et al. Diabetes mellitus in HIV-positive patients post-Pneumocystis pneumonia and the impact of aerosolized pentamidine. VI Int Conf AIDS San Francisco, 1:227(Th.B.422), 1990. OTHER REPORTS: Bozzette SA et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. NEJM 323: 1451-7, l990. Falloon J et al. The pharmacokinetics of atovaquone suspension in patients with HIV infection. Abstract 242, 1st Natl Conf on Hum Retrovir, 1993. Falloon J et al. Pharmacokinetics and safety of weekly dapsone and dapsone plus pyrimethamine for prevention of Pneumocystis pneumonia. Antimicrob Agents Chemother 30:1580-1587, 1994. Gagnon S et al. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the Acquired Immunodeficiency Syndrome - a double-blind, placebo-controlled trial. NEJM, 323:1444-50, l990. Hirschel B et al. A controlled study of inhaled pentamidine for primary prevention of PCP. NEJM 324: 1087-83, 1991. Kovacs A et al. CD4 T-lymphocyte counts and Pneumocystis carinii pneumonia in pediatric HIV infection. JAMA 265: 1698-703, 1991. King C et al. Survival, death, and desensitization to trimethhoprim-sulfamethoxazole (TMP/SMX). Abstract #388B, X Intl Conf AIDS, Yokohama, 1994. Leoung GS et al. Aerosolized pentamidine for prophylaxis against Pneumocystis carinii pneumonia - the San Francisco Community Prophylaxis Study. NEJM 323(12): 769-75, 1990. Lisman C et al. Aerosolized pentamidine as primary prophylaxis for Pneumocystis carinii pneumonia: efficacy, mortality and morbidity. AIDS 8:935-939, 1994. Masur H et al. Consensus statement on the use of corticosteroids as adjunctive therapy for Pneumocystis pneumonia in the acquired immunodeficiency syndrome. NEJM 323(21): 1500-4, 1990. Masur H. Prevention and treatment of pneumocystis pneumonia (review article). NEJM 327:1853-60, 1992. Safrin S eta l. Adjunctive folinic acid with trimethoprim- sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis 170:912-917, 1994. Copyright (c) 1993 - American Foundation for AIDS Research (AmFAR) - All Rights Reserved. Permission to reproduce for non-profit use granted with the condition that the source and date of the information be given, and that AmFAR be notified. Eric Fretz, Treatment Information Services, AmFAR. DISTRIBUTED BY GENA/aegis (714.248.2836 * 8N1/Full Duplex * v.34); taking you to the edge of the electronic AIDS-information frontier and beyond. ................................................................. CENTERS FOR DISEASE CONTROL AND PREVENTION HIV/AIDS PREVENTION CDC NATIONAL AIDS HOTLINE TRAINING BULLETIN ................................................................. March 16, 1995 #132 This is a statement from the National Institutes of Health (NIH) concerning two studies of therapies for AIDS-related infections. Two studies, done by the AIDS Clinical Trials Group (ACTG) of the National Institute of Allergy and Infectious Diseases (NIAID), of therapies for AIDS-related infections appear in the March 16 issue of The New England Journal of Medicine. Three Therapies Prevent Pneumonia (ACTG 081) In patients with advanced HIV infection, three treatments have similar effectiveness in preventing Pneumocystis carinii pneumonia (PCP). Investigators assessed the risks for developing PCP during 36 months of therapy among more than 800 patients with HIV and 200 or fewer CD4+ T cells per cubic millimeter of blood. CD4+ T cells are the infection-fighting cells targeted by HIV. The risk for developing PCP was 18 percent among patients taking trimethoprim- sulfamethoxazole (TMP/SMX), 17 percent for those receiving dapsone, and 21 percent for those on aerosolized pentamidine therapy. For patients with fewer than 100 CD4+ T cells, therapies that start with TMP/SMX or high dose dapsone are superior to treatments beginning with pentamidine. Authors note, however, that the greatest gains in preventing PCP will likely come from identifying more people at risk of the disease, rather than optimizing therapy for patients already receiving care. Fluconazole Prevents Fungal Infections (ACTG 981) Fluconazole was more effective than clotrimazole in preventing fungal infections in patients with advanced HIV infection, particularly those with 50 or fewer CD4+ T cells. In a substudy of ACTG 081 patients, researchers found that fluconazole reduced the frequency of cryptococcal meningitis and esophageal candidiasis, as well as superficial fungal infections. ................................................................. CENTERS FOR DISEASE CONTROL AND PREVENTION HIV/AIDS PREVENTION CDC NATIONAL AIDS HOTLINE TRAINING BULLETIN ................................................................. May 1, 1995 #141 This is an answer from the Centers for Disease Control and Prevention (CDC) to a question from the CDC National AIDS Hotline concerning the cause of PCP. NAH Question: Our Information Manual states that the organism which causes PCP is "most often thought to be protozoan in nature ... some scientists have suggested that it is caused by a fungus." Has that organism been positively identified yet? CDC Response: The organism, Pneumocystis carinii, causes pneumonia in immunodeficient persons. Genetically, it is a type of fungus. However, because most clinicians with expertise in Pneumocystis carinii pneumonia (PCP) are parasitologists (rather than mycologists) and the medicines used in treating PCP are antiparasitic (rather than antimycotic), Pneumocystis carinii may still be regarded as a parasite--even though this is not the most appropriate designation on a strictly technical basis.