Secondary Pneumocystis Carinii Pneumonia Prophylaxis Research Articles

A prospective multicentre study of discontinuing prophylaxis for opportunistic infections after effective antiretroviral therapy.

To assess the medium-term safety of discontinuing prophylaxis (primary or secondary) for opportunistic infections following an effective response to antiretroviral therapy. Participating clinical sites prospectively identified patients in whom the discontinuation of prophylaxis for any opportunistic infection was considered to be clinically indicated, although CD4 levels were not predefined. A follow-up report was subsequently sent every 6 months requesting information on changes in prophylaxis, antiretroviral drugs, new AIDS-defining events, and CD4 cell count results. Prophylaxis for Pneumocystis carinii pneumonia (PCP) was withdrawn in 524 patients (426 primary and 98 secondary prophylaxis), prophylaxis for Mycobacterium avium complex (MAC) was withdrawn in 28 patients (13 primary and 15 secondary), and prophylaxis for cytomegalovirus (CMV) retinitis was withdrawn in 10 patients. CD4 counts were generally maintained above accepted prophylaxis threshold levels during the period of follow up (95-98% of the time). Total follow up to last report or re-continuation of prophylaxis was 680 and 144 person-years for patients discontinuing primary and secondary PCP prophylaxis, respectively. No cases of PCP were reported, giving incidence rates of 0.0 (upper 95% confidence limit 0.4) and 0.0 (2.1) per 100 person-years. No cases of MAC were reported, but one patient had a recurrence of CMV retinitis. PCP prophylaxis was restarted in 30 patients; no patients restarted MAC or CMV prophylaxis. Previous studies have demonstrated a low risk of PCP in the short term following the withdrawal of prophylaxis in patients who have responded well to antiretroviral therapy. The present study suggests a continuing low level of risk with extended follow up, provided adequate CD4 count levels are maintained. The case of recurrent CMV retinitis in a patient with impressive immunological and virological response indicates the need for close monitoring of patients previously diagnosed with this condition.

Pneumocystis carinii pneumonia recurrence in HIV patients on highly active antiretroviral therapy: secondary prophylaxis.

The incidence and risk factors for Pneumocystis carinii pneumonia (PCP) recurrence were evaluated in 451 HIV-infected patients enrolled in the French Hospital Database on HIV who started highly active antiretroviral therapy (HAART) while receiving secondary PCP prophylaxis after a first episode occurring between January 1995 and December 1998. There were 18 episodes of recurrent PCP. On HAART, the CD4+ cell count increased to above 200 x 106/L in 274 patients, 51 of whom stopped PCP prophylaxis. None of these patients had PCP recurrences during 363 person-years (PY) of follow-up after the CD4+ cell count had reached 200 x 106/L (incidence rate [IR], 0.00 cases/100 PY; 95% confidence interval [CI], 0.00-0.82), and 37 PY of follow-up after the CD4+ cell count had reached 200 x 106/L and PCP prophylaxis had been discontinued (IR, 0.00 cases/100 PY; 95% CI, 0.00-7.84). The CD4+ cell count remained < 200 x 106/L in 177 patients; 9 patients stopped PCP prophylaxis, and 6 of these had a disease recurrence. Multivariate Cox analysis (time censored when CD4+ cell count > 200 x 106/L) showed that discontinuation of secondary prophylaxis (relative hazard [RH], 25.95; p <.0001) was associated with recurrence, whereas higher CD4+ cell counts during follow-up (RH, 0.39/50 x 106/L increment; p <.002) were protective.

Pneumocystis carinii Pneumonia Recurrence in HIV Patients on Highly Active Antiretroviral Therapy: Secondary Prophylaxis

Summary: The incidence and risk factors for Pneumocystis carinii pneumonia (PCP) recurrence were evaluated in 451 HIV-infected patients enrolled in the French Hospital Database on HIV who started highly active antiretroviral therapy (HAART) while receiving secondary PCP prophylaxis after a first episode occurring between January 1995 and December 1998. There were 18 episodes of recurrent PCP. On HAART, the CD4+ cell count increased to above 200 × 106/L in 274 patients, 51 of whom stopped PCP prophylaxis. None of these patients had PCP recurrences during 363 person-years (PY) of follow-up after the CD4+ cell count had reached 200 × 106/L (incidence rate [IR], 0.00 cases/100 PY; 95% confidence interval [CI], 0.00-0.82), and 37 PY of follow-up after the CD4+ cell count had reached 200 × 106/L and PCP prophylaxis had been discontinued (IR, 0.00 cases/100 PY; 95% CI, 0.00-7.84). The CD4+ cell count remained < 200 × 106/L in 177 patients; 9 patients stopped PCP prophylaxis, and 6 of these had a disease recurrence. Multivariate Cox analysis (time censored when CD4+ cell count > 200 × 106/L) showed that discontinuation of secondary prophylaxis (relative hazard [RH], 25.95; p < .0001) was associated with recurrence, whereas higher CD4+ cell counts during follow-up (RH, 0.39/50 × 106/L increment; p < .002) were protective.

Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV-1 infection

Highly active antiretroviral therapy (HAART) has improved rates of CD4-lymphocyte recovery and decreased the incidence of HIV-1-related morbidity and mortality. We assessed whether prophylaxis against Pneumocystis carinii pneumonia (PCP) can be safely discontinued after HAART is started. We investigated 7333 HIV-1-infected patients already enrolled in EuroSIDA, a continuing prospective observational cohort study in 52 centres across Europe and Israel. We did a person-years analysis of the rate of discontinuation of PCP prophylaxis and of the incidence of PCP after the introduction of HAART into clinical practice from July, 1996. The rate of discontinuation of primary and secondary PCP prophylaxis increased up to 21.9 discontinuations per 100 person-years of follow-up after March, 1998. 378 patients discontinued primary (319) or secondary (59) prophylaxis a median of 10 months after starting HAART. At discontinuation for primary and secondary prophylaxis, respectively, the median CD4-lymphocyte counts were 274 cells/microL and 270 cells/microL, the median plasma HIV-1 RNA load 500 copies/mL, and the median lowest recorded CD4-lymphocyte counts 123 cells/microL and 60 cells/microL. During 247 person-years of follow-up, no patient developed PCP (incidence density 0 [95% CI 0-1.5]). The risk of PCP after stopping primary prophylaxis, especially in patients on HAART with a rise in CD4-lymphocyte count to more than 200 cells/microL, is sufficiently low to warrant discontinuation of primary PCP prophylaxis. Longer follow-up is needed to confirm a similarly low risk for stopping secondary PCP prophylaxis.

Hospital service interventions and improving survival of AIDS patients St Mary's Hospital, London, 1982-1991.

The relationship between changes in hospital service interventions at St Mary's Hospital, London, reduced case fatality for patients with their first episode of Pneumocystis carinii pneumonia (PCP) and improved survival from diagnosis of AIDS was investigated for the period 1982-1991. Multivariate logistic regression models identified factors independently associated with episode survival; for those patients who survived their first episode of PCP, survival from time of diagnosis of AIDS was analysed using multivariate Cox's proportional hazards models. The case-fatality rate after 1987 was significantly lower for the 159 subjects. Median survival from diagnosis of AIDS increased significantly from 142 days to 554 days (P=0.01). Improved survival of first episode of PCP was associated with it being the index diagnosis and having a haemoglobin at diagnosis of PCP greater than 12 g/dl. The presence of a concurrent AIDS-defining condition in patients who presented with an A-a gradient equal to or greater than 40 mmHg was associated with reduced episode survival, especially before 1987. For the 126 individuals who survived their first episode of PCP, death rates were lowest in patients treated with primary or secondary PCP prophylaxis and those who received zidovudine since their first episode of PCP. Survival in patients with HIV disease is better in patients who receive appropriate antiretroviral treatment of HIV infection and timely treatment of opportunistic illnesses. Early diagnosis of HIV-1 infection with early diagnosis and treatment of first episode of PCP was associated with improved episode survival. Subsequent medical follow up combined with PCP prophylaxis and zidovudine were significantly associated with long-term survival.

Co-trimoxazole desensitization in HIV-seropositive patients.

Co-trimoxazole (trimethoprim-sulphamethoxazole) is an effective prophylactic agent against Pneumocystis carinii pneumonia (PCP). However, it is associated with a high frequency of adverse reactions in immunocompromised patients which may preclude its use. Fourteen patients with a definite history of adverse reactions to co-trimoxazole on standard PCP prophylactic dosage were selected for desensitization using a regimen of gradual incremental exposure over an 11-day period. Eight (57.1%) were successfully desensitized and have continued on oral co-trimoxazole at maximum 21 months' follow-up. This report demonstrates that oral desensitization as an outpatient procedure is an effective and safe option for both primary and secondary PCP prophylaxis in HIV-seropositive patients with previous adverse drug reactions.

Prevention of Pneumocystis carinii pneumonia: who are we missing?

To obtain population-based information on the characteristics of persons who were not receiving chemoprophylaxis against Pneumocystis carinii pneumonia (PCP) by examining the use of primary and secondary PCP prophylaxis among San Francisco residents whose AIDS-defining opportunistic illness was PCP in 1993. Retrospective medical record review. Medical charts were obtained from San Francisco hospitals and outpatient facilities at which AIDS patients received their initial AIDS diagnosis. San Francisco residents whose AIDS-defining opportunistic illness was PCP in 1993. Use of primary and secondary PCP prophylaxis. Of the 326 eligible patients, 35% received primary PCP prophylaxis. Non-whites were significantly less likely to have received primary PCP prophylaxis than white patients [22 versus 40%, respectively; odds ratio (OR), 0.49; 95% confidence intervals (CI), 0.28-0.87]. Uninsured individuals-were also less likely to have received primary PCP prophylaxis than those with insurance (18 versus 41%; OR, 0.35; 95% CI, 0.17-0.73). The sociodemographic characteristics of patients who did and did not receive secondary PCP prophylaxis did not differ significantly. The most frequently cited reasons for not receiving primary PCP prophylaxis were that patients were unaware of their infection with HIV or were not receiving regular medical care. Barriers to receipt of PCP prophylaxis exist and are resulting in cases of preventable disease and unnecessary medical costs. Interventions to increase counseling, testing, and referral to medical care for persons at high risk for HIV infection are needed.

Validating Literature-based Models with Direct Clinical Trial Results

To compare literature-based estimates of the cost-effectiveness ratios of strategies for secondary prophylaxis of Pneumocystis carinii pneumonia (PCP) in AIDS patients with estimates obtained using data from a recent comparative clinical trial. A decision-analytic Markov model with data on drug efficacy and toxicity from both the medical literature and a national randomized clinical trial. Drug costs were from average wholesale prices. Discounted life expectancy, total direct medical costs, and cost-effectiveness were projected in dollars per year of life saved (YLS). Hypothetical for the literature-based model, then the clinical trial results from the multicenter AIDS Clinical Trials Group (ACTG Protocol 021). Patients with AIDS and a prior episode of PCP. Strategies included no prophylaxis, TMP-SMX (160/800 mg) daily, or aerosolized pentamidine (300 mg) monthly. Patients experiencing major toxic reactions to either medication would cross over to the other agent. In the literature-based model no prophylaxis was associated with a projected life expectancy of 1.430 years, and total direct cost of $42,080. TMP-SMX increased life expectancy to 2.051 years and cost to $42,300; for aerosolized pentamidine life expectancy was 2.066 years and cost $43,960. TMP-SMX had an incremental cost-effectiveness ratio of $350 per YLS compared with no prophylaxis; the incremental ratio for aerosolized pentamidine was $2,950 per YLS when compared with no prophylaxis, but rose to $110,880 per YLS compared with TMP-SMX. When data from ACTG clinical trial 021 were utilized in the model, the incremental cost-effectiveness ratio for TMP-SMX compared with no prophylaxis was $720 per YLS; aerosolized pentamidine was not cost-effective, and was "dominated" by TMP-SMX because it was associated with higher costs and shorter life expectancy. Literature-based cost-effectiveness models are useful in developing health policy before clinical trials are completed. Clinical trial results, when available, can be used to validate and revise these models. For secondary PCP prophylaxis in AIDS patients, TMP-SMX is substantially more cost-effective than aerosolized pentamidine.

Better efficacy of twice-monthly than monthly aerosolised pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with AIDS. An Italian multicentric randomised controlled trial

The aim of this multicentric randomised controlled trial was to evaluate long-term efficacy and safety of once-monthly versus twice-monthly 300 mg aerosolized pentamidine (AP) as secondary prophylaxis of Pneumocystis carinii pneumonia (PCP). We randomised 205 patients with a previous confirmed episode of PCP (107 treated with 300 mg once-monthly AP, and 98 with 300 mg twice monthly AP); the median review period was 232 days. Kaplan-Meier method and Cox's hazard regression model were used for analysis. The main outcome assessments were PCP recurrence, survival and incidence of drug toxicity. The two groups were balanced for prognostic predictors. In the once-monthly AP group, 14 relapses of confirmed PCP were observed, while five occurred in the twice-monthly AP group; the crude relative risk (RR) was 2.69 (95% CI 1.002-7.236, P=0.0496) and the adjusted RR accounting for prognostic predictors was 2.62 (95% CI 0.92-7.5, P=0.071). Death occurred in 36 of 26 patients respectively (adjusted RR 1.32, 95% CI 0.8-2.18, P=0.28). Two patients interrupted the study because of intolerance to AP (one in each group), and severe coughing occurred in two patients (one in each group). At the end of the study, pulmonary function tests were not changed compared with baseline and were the same between the two groups. Our study suggests that 300 mg twice-monthly AP is more effective than 300 mg once-monthly AP as secondary prophylaxis of PCP.

Randomized Study of Sulfamethoxazole-trimethoprim versus Aerosolized Pentamidine for Secondary Prophylaxis of Pneumocystis carinii Pneumonia in Patients with AIDS

In a prospective, randomized open-label trial, the efficacy of sulfamethoxazole-trimethoprim (SMX-TMP) 400/80 mg b.i.d. was compared with the efficacy of aerosolized pentamidine (AP) 60 mg every 2nd week as secondary prophylaxis (SP) against recurrence of Pneumocystis carinii pneumonia (PCP) in AIDS patients. 94 patients participated in the study, 47 in each group. The patients were observed for a mean period of 17.2 months. PCP recurred in the AP group in 8 cases, while 1 relapse occurred in the SMX-TMP group. The one-year cumulative relapse rate was 9.0% (95% CI 0-19%) in the AP group compared with 2.4% (95% CI 0-8%) in the SMX-TMP group (p < 0.05). The odds ratio was 4.2 (95% CI 0.5-39.8) in favour of SMX-TMP. Furthermore, we found a tendency towards a protective effect against toxoplasmosis in the SMX-TMP group, though there was no difference in survival between the two groups. There was no statistical difference in frequency of crossover from one therapy form to the other. Based on these data we recommend SMX-TMP for secondary PCP prophylaxis.

Randomized trial of dapsone and aerosolized pentamidine for the prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis

purpose: Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis are the most frequent pulmonary and central nervous system opportunistic infections associated with human immunodeficiency virus (HIV) infection. We designed a prospective study to compare the effects of aerosolized pentamidine and dapsone in the prophylaxis of these infections in HIV-infected persons with CD4+ lymphocyte counts less than 250/mm 3. patients and methods: Two hundred seventy-eight patients seropositive for HIV who had acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex were randomly assigned to receive intermittent dapsone (100 mg twice weekly) or aerosolized pentamidine (100 mg every 2 weeks). The proportion of patients remaining free of PCP or toxoplasmosis was analyzed with the log-rank test as a function of time, as were the effects of zidovudine or prophylaxis on survival. results: Dapsone and aerosolized pentamidine demonstrated similar efficacy in the primary and secondary prophylaxis of PCP, with 15 (18%) failures among patients receiving dapsone compared to 15 (14%) among those receiving aerosolized pentamidine (p = 0.4), after a mean length of follow-up of 42 and 44 weeks, respectively. Dapsone was more effective in the primary prophylaxis of toxoplasmic encephalitis, with six toxoplasmic encephalitis events occurring among those receiving aerosolized pentamidine, compared to none among those taking dapsone (p = 0.01). Primary prophylaxis for PCP was more effective than secondary prophylaxis with either therapy. Zidovudine therapy did not prevent PCP yet prolonged the PCP-free interval for those in whom either prophylactic therapy failed. Kaplan-Meier estimates did not show a difference in survival between the patients receiving either therapy, yet zidovudine use was associated with improved survival, independent of race and risk factor (Cox proportional hazards model, p = 0.001). The 1-month survival for patients developing PCP despite prophylaxis was better with those in whom dapsone failed than it was for those in whom aerosolized pentamidine failed (p = 0.08). conclusion: Dapsone is as effective as aerosolized pentamidine in preventing PCP and has the advantage of a lower cost, easier administration, and possibly an additional preventive effect against toxoplasmosis. Zidovudine prolongs the PCP-free interval for patients receiving prophylaxis, regardless of which prophylactic agent is used.

Decreased Efficacy of Inhaled Pentamidine in the Prevention of Pneumocystis carinii Pneumonia Among HIV-infected Patients With Severe Immunodeficiency

To determine the relationship between the degree of immune deficiency and the risk of Pneumocystis carinii pneumonia (PCP) among HIV-infected patients receiving inhaled pentamidine prophylaxis. Retrospective chart review. AIDS clinic of inner-city hospital. Patients attending inhaled pentamidine clinic between 1989 and 1991. Review of medical records of patients receiving inhaled pentamidine, 300 mg/month, via nebulizer (Respirgard II) as primary or secondary prophylaxis of PCP. Statistical analysis of lymphocyte subset results and selected clinical data. Ten of 57 patients developed PCP during the period of analysis. Patients with CD4 counts less than 60/mm3 were significantly more likely to develop PCP (p = 0.01; Fisher's exact test) with a relative risk of 7.55 compared to patients with CD4 lymphocyte counts greater than 60/mm3. Failure of inhaled pentamidine prophylaxis is seen almost exclusively among patients with CD4 lymphocyte counts below 60/mm3.

Bilateral Pneumothoraces Hasten Mortality in AIDS Patients Receiving Secondary Prophylaxis with Aerosolized Pentamidine: Association with a Lower Dco Prior to Receiving Aerosolized Pentamidine

We have administered aerosolized pentamidine (AP) to 48 AIDS patients for secondary prophylaxis of Pneumocystis carinii pneumonia (PCP). Pentamidine 60 mg was administered by ultrasonic nebulization (Fisoneb) five times during the first two weeks and then every two weeks. The mean follow-up was 343 +/- 22 days. PCP recurred in ten patients, 297 +/- 33 days after starting AP therapy. All responded to anti-Pneumocystis therapy but two patients died of unrelated reasons (20 percent mortality). Five patients developed bilateral pneumothoraces 260 +/- 35 days after starting AP therapy. Recurrence of PCP could be documented in only one patient. All died 66 +/- 27 days after the onset of the first pneumothorax. Only 5 of 33 patients without recurrence of pneumonia or pneumothorax died during the study period (15 percent mortality). No association was found between the development of pneumothorax and age, smoking, previous respiratory or infectious problems, time from last PCP and the initiation of AP therapy, and treatment duration of last PCP. Patients with pneumothoraces had a significantly lower Dco (58.6 +/- 2.6 percent predicted) prior to AP therapy than patients with recurrence of PCP without pneumothoraces (81.1 +/- 2.1 percent predicted) or patients with no recurrence of PCP (67 +/- 2.5 percent predicted) (p less than 0.05, ANOVA). In conclusion, bilateral pneumothoraces are associated with a hastened mortality in patients receiving AP for secondary prophylaxis of PCP. Low Dco before AP therapy is associated with an increased risk of bilateral pneumothoraces in patients treated with AP for secondary prophylaxis of PCP.

Trends in mortality among AIDS patients in Amsterdam, 1982–1988

In this study we evaluated the survival of 515 AIDS patients diagnosed in Amsterdam between 1982 and 1988 and followed-up until April 1990. Non-resident patients survived for a shorter period than resident patients (median survival time 10 versus 16 months). Residents had a 1-, 2- and 3-year survival of 56.1, 33.0 and 17.2%, respectively. Heterosexual intravenous drug users tended to have a better survival than homosexual men, although this was not significant. The survival time was longer for AIDS patients less than 30 years of age at diagnosis and varied for the different clinical manifestations leading to AIDS diagnosis. We calculated the 1- and 2-year survival probability by year of diagnosis for patients initially presenting with a Pneumocystis carinii pneumonia (PCP). The 1-year survival improved greatly in 1986 and continued to rise in the following years. The 2-year survival was similar in 1986 and 1987 (26.8 versus 28.2%) but increased in 1988 (38.9%). We conclude that besides better clinical experience and diagnostic methods, this improvement in prognosis could be explained by the start of secondary prophylaxis for PCP in 1985 and the introduction of zidovudine therapy in 1987.

Upper lobe relapse ofPneumocystis carinii Pneumonia during aerosolized pentamidine prophylaxis

A patient with a history of Pneumocystis carinii pneumonia (PCP) inhaled aerosolized pentamidine (AP) for secondary prophylaxis of PCP. Nine months after the first PCP episode he presented with pulmonary upper-lobe infiltrations demonstrated by chest x-ray, and bronchoalveolar lavage confirmed the diagnosis of PCP. The clinical course and possible explanations for this unusual form of PCP are presented. The case emphasizes the importance of clinical controls for early diagnosis of relapse of PCP in patients inhaling aerosolized pentamidine. Monitoring of serum lactate dehydrogenase levels appeared to be important in the follow-up of the patient described.

Pneumocystis carinii pneumonia in Stockholm, Sweden: treatment, outcome, one-year-follow-up and pyrimethamine prophylaxis.

In 33 consecutive AIDS patients with a first episode of Pneumocystis carinii pneumonia (PCP) we evaluated treatment, outcome, recurrence rate and pyrimethamine as chemoprophylaxis in a 1-year follow-up. Only 2 patients had a CD4 lymphocyte cell count greater than 0.2 X 10(9)/l. Trimethoprim-sulfamethoxazole (TMP-SMX) was initially given to 32 patients but in 20 of these patients severe adverse reactions caused us to discontinue treatment. Of these 20 patients 11 were started on i.v./i.m. pentamidine but in 6 adverse reactions forced us to withdraw pentamidine. Patients were retrospectively divided with regard to duration of therapy into 2 groups. We could not find any difference between patients in Group 1 treated for less than or equal to 14 days and patients in Group 2 treated for greater than 14 days when comparing outcome, number of recurrences and mean time until recurrence. In 16/21 patients given only TMP-SMX initially in a high dose (means = 16 mg trimethoprim/kg/day), dose reduction was performed to means = 10.5 mg trimethoprim/kg/day after a mean time of 6.9 days. The case-fatality rate for these patients was 10% (2/21) and the overall case-fatality rate was 15% (5/33). We chose pyrimethamine (50-175 mg/week) as secondary prophylaxis for PCP. At 1-year follow-up another 16 patients had died (21/32) and 9/27 (33%) discharged patients had had one recurrence each of PCP. All recurrences occurred among patients treated with only TMP-SMX for the acute episode of PCP. Of these 27 discharged patients 23 had been given pyrimethamine and 8 (36%) of these had experienced a recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)