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Background

Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with CD4 counts of less than 200 cells/mm3. This study examines the proportion of patients in the TREAT Asia HIV Observational Database (TAHOD) receiving PCP prophylaxis, and its effect on PCP and mortality.

Methods

TAHOD patients with prospective follow up had data extracted for prophylaxis using co-trimoxazole, dapsone or pentamidine. The proportion of patients on prophylaxis was calculated for each calendar year since 2003 among patients with CD4 counts of less than 200 cells/mm3. The effect of prophylaxis on PCP and survival were assessed using random-effect Poisson regression models.

Results

There were a total of 4050 patients on prospective follow up, and 90% of them were receiving combination antiretroviral therapy. Of those with CD4 counts of less than 200 cells/mm3, 58% to 72% in any given year received PCP prophylaxis, predominantly co-trimoxazole. During follow up, 62 patients developed PCP (0.5 per 100 person-years) and 169 died from all causes (1.36/100 person-years). After stratifying by site and adjusting for age, CD4 count, CDC stage and antiretroviral treatment, those without prophylaxis had no higher risk of PCP, but had a significantly higher risk of death (incident rate ratio 10.8, p < 0.001). PCP prophylaxis had greatest absolute benefit in patients with CD4 counts of less than 50 cells/mm3, lowering mortality rates from 33.5 to 6.3 per 100 person-years.

Conclusions

Approximately two-thirds of TAHOD patients with CD4 counts of less than 200 cells/mm3 received PCP prophylaxis. Patients without prophylaxis had significantly higher mortality, even in the era of combination ART. Although PCP may be under-diagnosed, these data suggest that prophylaxis is associated with important survival benefits.

Pneumocystis carinii pneumonia (PCP) remains a serious opportunistic infection in HIV infected individuals. Seasonal changes in climate are associated with changes within individual susceptibility to infection. The possibility of monthly variability in the incidence of PCP was therefore examined by means of a cohort study of a database of 8640 HIV infected individuals attending the Chelsea and Westminster Hospital. There were 792 cases of PCP diagnosed since 1985. A marked decline was observed in the incidence of PCP in mid-1992 coincident with the introduction of PCP prophylaxis. There was a further decline in 1996 after the introduction of highly active antiretroviral therapy. Despite no significant monthly variation in the mean attendance to clinic and CD4 count, both new and all cases of PCP were higher in January than in other months (15.9% and 14.5% of all cases, respectively). A correlation with low rainfall in January and new cases of PCP was observed. These data are consistent with an influence of climatic conditions on the presentation of PCP. The diagnosis of PCP is more common in winter months suggesting that this is a transmissible infection.

We conducted an open prospective clinical trial to evaluate the efficacy and toxicity of trimethoprim-sulfamethoxazole given as one double-strength tablet thrice weekly for primary and secondary prophylaxis of Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus-infected (HIV+) patients. A total of 104 HIV+ patients were evaluated, with 74 being in the primary prophylaxis group and 30 being in the secondary prophylaxis group. All except six patients received concomitant zidovudine; five patients on primary prophylaxis and one patient on secondary prophylaxis refused zidovudine. There were 70 patients evaluated for the efficacy of primary prophylaxis. The mean CD4 count was 124.4 +/- 110.1 cells per microliter. The mean follow-up time was 11.8 +/- 5.8 months (median, 12 months; range, 1 to 32 months). Two noncompliant patients developed PCP after 1 and 3 months of chemoprophylaxis. The failure rate (under the intention to treat principle) was 2 of 70 patients (2.9%; 95% confidence interval, 0.35 to 10%), or 1 per 413 patient-months of observation. There were 27 patients evaluated for the efficacy of secondary prophylaxis. The mean follow-up time was 12.4 +/- 7.2 months (median, 11 months; range, 1 to 29 months). Two patients, one of whom was noncompliant, were treatment failures, developing PCP after 14 and 15 months of chemoprophylaxis; this gave a failure rate of 2 of 27 patients (7.4%; 95% confidence interval, 0.9 to 24.3%), or 1 per 167 patient-months of observation. Adverse reactions sufficient to permanently terminate therapy occurred in 9 of 104 patients (8.7%; 95% confidence interval, 4 to 15.7%) overall. The serum trimethoprim, sulfamethoxazole, and N4-acetyl-sulfamethoxazole concentrations measured by high-pressure liquid chromatography were uniformly low. One double-strength tablet of trimethoprim-sulfamethoxazole taken weekly on Monday, Wednesday, and Friday appeared to be well tolerated and efficacious for the prophylaxis of PCP in HIV+ patients at high risk and deserves further investigation.

Hyperimmune anti-human immunodeficiency virus immunoglobulin (HIVIG) is an intravenous immunoglobulin prepared from HIV-infected asymptomatic donors with a CD4 cell count greater than 400 cells/microl and a high titer of antibody to HIV-1 p24 protein. Twelve persons with AIDS received four doses of HMG (two at 50 mg/kg of body weight and then two at 200 mg/kg) every 28 days. Pharmacokinetics were evaluated by measurement of anti-p24 antibody. HIVIG was well tolerated, and all participants completed the study. Three subjects who were not receiving Pneumocystis carinii pneumonia (PCP) prophylaxis developed PCP. The mean value for HIVIG clearance was 3.02 ml/kg/day at 50 mg/kg and 3.65 ml/kg/day at 200 mg/kg (P = 0.027); the mean trough antibody titers (reciprocal units) were 1,442 and 4,428, respectively. This study indicates that high titers of anti-p24 antibody can be maintained with a monthly administration schedule of HIVIG and that short-term safety is acceptable. Comparisons to evaluate the therapeutic potential of HIVIG are justified.

Background

HIV viral load (VL) is currently not part of the criteria for Pneumocystis jirovecii pneumonia (PCP) prophylaxis discontinuation, but suppression of plasma viremia with antiretroviral therapy may allow for discontinuation of PCP prophylaxis even with CD4 count <200 cells/µL.

Methods

A systematic review was performed to determine the incidence of PCP in HIV-infected individuals with CD4 count <200 cells/µL and fully suppressed VL on antiretroviral therapy but not receiving PCP prophylaxis.

Results

Four articles examined individuals who discontinued PCP prophylaxis with CD4 count <200 cells/µL in the context of fully suppressed VL on antiretroviral therapy. The overall incidence of PCP was 0.48 cases per 100 person-years (PY) (95% confidence interval (CI) (0.06–0.89). This was lower than the incidence of PCP in untreated HIV infection (5.30 cases/100 PY, 95% CI 4.1–6.8) and lower than the incidence in persons with CD4 count <200 cells/µL, before the availability of highly active antiretroviral therapy (HAART), who continued prophylaxis (4.85/100 PY, 95% CI 0.92–8.78). In one study in which individuals were stratified according to CD4 count <200 cells/µL, there was a greater risk of PCP with CD4 count ≤100 cells/µL compared to 101–200 cells/µL.

Conclusion

Primary PCP prophylaxis may be safely discontinued in HIV-infected individuals with CD4 count between 101–200 cells/µL provided the VL is fully suppressed on antiretroviral therapy. However, there are inadequate data available to make this recommendation when the CD4 count is ≤100 cells/µL. A revision of guidelines on primary PCP prophylaxis to include consideration of the VL is merited.

Introduction

Opportunistic infections can occur in up to 40% of people with HIV infection and a CD4 count less than 250/mm3, although the risks are much lower with use of highly active antiretroviral treatment.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of prophylaxis for Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis? What are the effects of antituberculosis prophylaxis in people with HIV infection? What are the effects of prophylaxis for disseminated Mycobacterium avium complex (MAC) disease for people with, and without, previous MAC disease? What are the effects of prophylaxis for cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV)? What are the effects of prophylaxis for invasive fungal disease in people with, and without, previous fungal disease? What are the effects of discontinuing prophylaxis against opportunistic pathogens in people on highly active antiretroviral treatment (HAART)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 43 systematic reviews, RCTs, or observational studies that met our inclusion criteria.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: aciclovir; antituberculosis prophylaxis; atovaquone; azithromycin (alone or plus rifabutin); clarithromycin (alone, or plus rifabutin and ethambutol); discontinuing prophylaxis for CMV, MAC, and PCP; ethambutol added to clarithromycin; famciclovir; fluconazole; isoniazid; itraconazole; oral ganciclovir; rifabutin (alone or plus macrolides); trimethoprim–sulfamethoxazole; and valaciclovir.

Key Points

Opportunistic infections can occur in up to 40% of people with HIV infection and a CD4 count less than 250/mm3, although the risks are much lower with use of highly active antiretroviral treatment (HAART). HAART has reduced the rate of Pneumocystis jirovecii pneumonia (PCP), toxoplasmosis, and other opportunistic infections, so the absolute benefits of prophylactic regimens for opportunistic infections are probably smaller in people with HIV who are also taking HAART, and even smaller for those whose HIV is suppressed.

Primary prophylaxis with trimethoprim–sulfamethoxazole may reduce the risk of PCP, and has been found to be more effective than pentamidine or dapsone. Atovaquone may prevent PCP in people who cannot tolerate trimethoprim−sulfamethoxazole.We don't know whether these drugs prevent toxoplasmosis as we found few RCTs, but there is consensus that standard trimethoprim–sulfamethoxazole prophylaxis or dapsone should offer adequate coverage for toxoplasmosis.

Tuberculosis can be prevented by standard primary prophylaxis in people who are tuberculin skin test positive. Short-term combination treatment has similar efficacy to long-term isoniazid monotherapy, but is associated with a greater risk of adverse effects.

Azithromycin or clarithromycin reduce the risk of disseminated Mycobacterium avium complex (MAC) disease as primary prophylaxis for people without prior MAC disease. Adding rifabutin may also be beneficial in this population, but is also associated with an increased risk of adverse effects. There is consensus that secondary prophylaxis with clarithromycin plus ethambutol decreases the risk of relapse in people with previous MAC disease. It remains unclear whether adding rifabutin to the dual drug regimen confers additional benefit as secondary prophylaxis, and the three-drug combination increases adverse effects.

Aciclovir as secondary prophylaxis reduces the risk of herpes simplex virus (HSV) and varicella zoster virus infection (VZV) and all-cause mortality. Valaciclovir may reduce the risk of recurrent HSV infection, but it may be associated with serious adverse effects.There is consensus that famciclovir is effective as secondary prophylaxis against HSV or VZV and that ganciclovir is effective as secondary prophylaxis against CMV, HSV, or VZV.

Fluconazole and itraconazole as primary prophylaxis may reduce the risk of invasive fungal infections, but azoles have been associated with potentially serious interactions with other drugs. As secondary prophylaxis, itraconazole seems effective in reducing relapse of Penicillium marneffei, but seems less effective than fluconazole at reducing recurrence of cryptococcal meningitis.

In people who have responded to HAART and have a CD4 cell count greater than 100/mm3 to 200/mm3 (depending on the condition), discontinuation of primary or secondary prophylactic treatment for PCP, toxoplasmosis, MAC, herpes virus, or invasive fungal disease infection seems safe.

Accompanying the increased use of biologic and non-biologic antirheumatic agents, patients with RA have been exposed to an increased risk of Pneumocystis jirovecii infection, which causes acute fulminant P. jirovecii pneumonia (PCP). Mortality in this population is higher than in HIV-infected individuals. Several guidelines and recommendations for HIV-infected individuals are available; however, such guidelines for RA patients remain less clear. Between 2006 and 2008 we encountered a clustering event of P. jirovecii infection among RA outpatients. Through our experience with this outbreak and a review of the recent medical literature regarding asymptomatic colonization and its clinical significance, transmission modes of infection and prophylaxis of PCP, we have learned the following lessons: PCP outbreaks among RA patients can occur through person-to-person transmission in outpatient facilities; asymptomatic carriers serve as reservoirs and sources of infection; and short-term prophylaxis for eradication of P. jirovecii is effective in controlling PCP outbreaks among RA outpatients.

Introduction

Opportunistic infections can occur in up to 40% of people with HIV infection and a CD4 count less than 250/mm3, although the risks are much lower with use of highly active antiretroviral treatment.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of prophylaxis for P carinii pneumonia (PCP) and toxoplasmosis? What are the effects of antituberculosis prophylaxis in people with HIV infection? What are the effects of prophylaxis for disseminated M avium complex (MAC) disease for people with, and without, previous MAC disease? What are the effects of prophylaxis for cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV)? What are the effects of prophylaxis for invasive fungal disease in people with, and without, previous fungal disease? What are the effects of discontinuing prophylaxis against opportunistic pathogens in people on highly active antiretroviral treatment (HAART)? We searched: Medline, Embase, The Cochrane Library and other important databases up to December 2004 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 61 systematic reviews, RCTs, or observational studies that met our inclusion criteria.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: acyclovir; antituberculosis prophylaxis; atovaquone; azithromycin (alone or plus rifabutin); clarithromycin (alone, or plus rifabutin and ethambutol, or plus clofazimine); clofazimine plus ethambutol; discontinuing prophylaxis for CMV, MAC, and PCP; ethambutol added to clarithromycin plus clofazimine; famciclovir; fluconazole; isoniazid; itraconazole; oral ganciclovir; rifabutin (alone or plus macrolides); trimethoprim-sulfamethoxazole; and valaciclovir.

Key Points

Opportunistic infections can occur in up to 40% of people with HIV infection and a CD4 count < 250/mm3, although the risks are much lower with use of highly active antiretroviral treatment.

Trimethoprim-sulfamethoxazole or azithromycin may reduce the risk of PCP, but have not been shown to reduce toxoplasmosis infection. Atovaquone may prevent PCP and toxoplasmosis in people who cannot take trimethoprim−sulfamethoxazole, although we don't know this for sure.

Tuberculosis can be prevented by standard prophylaxis in people who are tuberculin skin test positive, but not in those who are tuberculin skin test negative. Short-term combination treatment has similar efficacy to long-term isoniazid monotherapy, but has greater risk of adverse effects.

Azithromycin or clarithromycin may reduce the risk of disseminated Microbacterium avium complex (MAC) disease in people without prior MAC disease. Adding rifabutin may reduce the risk of MAC disease, while adding ethambutol decreases the risk of relapse, compared with other antibiotic regimens.Combination treatment with clarithromycin plus clofazimine may increase mortality and is usually avoided.

Aciclovir reduces the risk of herpes simplex virus (HSV) and varicella zoster virus infection and overall mortality, but has not been shown to reduce cytomegalovirus (CMV) infection. Valaciclovir and ganciclovir may reduce the risk of CMV infection, but may be associated with serious adverse effects.

Fluconazole and itraconazole may reduce the risk of invasive fungal infections or their relapse, but can cause serious adverse effects.

In people with a CD4 cell count above 100−200/mm3, discontinuation of prophylactic treatment may not increase the risk of PCP, toxoplasmosis or MAC infection.

Dapsone, administered at various doses and schedules, has been proven to be a safe and effective alternative to trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii pneumonia (PCP) in adults with human immunodeficiency virus (HIV) infection. Dapsone is also recommended by the Centers for Disease Control for PCP prophylaxis in HIV-infected children. However, the suggested dosage regimen is based upon clinical experience with children with leprosy and dermatitis herpetiformis rather than pharmacokinetic and pharmacodynamic data obtained from the target patient population. In order to determine a rational dosage regimen that could be tested in clinical studies aimed at the evaluation of dapsone for the prevention of PCP in HIV-infected children, we studied the pharmacokinetics of dapsone following a 2-mg/kg of body weight oral dose in twelve HIV-positive children aged 9 months to 9 years. Plasma was collected at the following times after dapsone administration: 0, 2, 4, 6, 12, 24, 48, 72, and 96 h. The levels of dapsone in plasma were determined by high-performance liquid chromatography. Data were analyzed by noncompartmental methods. Expressed as means +/- standard deviations (ranges), the pharmacokinetic parameters were as follows: peak concentration in plasma, 1.12 +/- 0.48 (0.44 to 1.81) mg/liter; time to peak concentration in plasma, 3.8 +/- 1.3 (2 to 6) h; half-life at elimination phase, 24.2 +/- 7.1 (14.4 to 35.0) h; clearance from plasma divided by bioavailability (CL/F), 1.15 +/- 0.67 (0.37 to 2.63) ml/min/kg; and volume of distribution divided by bioavailability (V/F), 2.25 +/- 1.20 (1.00 to 4.57) liters/kg. Oral CL correlated negatively with age (r = 0.614 and P = 0.034), as did V (r = 0.631 and P = 0.028). As a consequence of the high interindividual variability in growth retardation, pharmacokinetic parameters correlated with measures of body development better than they did with age (e.g., for CL/F to height, r = 0.765 and P = 0.004, and for V/F to height, r = 0.748 and P = 0.005). Since oral CL from plasma and V were positively and highly correlated (r = 0.898 and P = 0.0001), a lower absolute F may be the cause, in part, of higher values for CL/F and V/F in smaller children. The results of this study warrant the testing of a 2-mg/kg dose of dapsone administered twice or thrice weekly to HIV-infected children. The monitoring of drug levels in plasma and dosage adjustment may be necessary for smaller children.

Background

Despite the effectiveness of prophylaxis, Pneumocystis jirovecii pneumonia (PCP) continues to be the most common serious opportunistic infection among HIV-infected persons. We describe factors associated with nonadherence to primary PCP prophylaxis.

Methodology/Principal Findings

We used 2000–2004 data from the Supplement to HIV/AIDS Surveillance (SHAS) project, a cross-sectional interview project of HIV-infected persons ≥18 years conducted in 18 states. We limited the analysis to persons who denied having prior PCP, reported having a current prescription to prevent PCP, and answered the question “In the past 30 days, how often were you able to take the PCP medication(s) exactly the way your doctor told you to take them?” We used multivariable logistic regression to describe factors associated with nonadherence. Of 1,666 subjects prescribed PCP prophylaxis, 305 (18.3%) were nonadherent. Persons were more likely to be nonadherent if they reported using marijuana (adjusted odds ratio [aOR] = 1.6, 95% confidence interval [CI] = 1.1–2.4), non-injection drugs other than marijuana (aOR = 1.5, 95% CI = 1.0–2.1), or injection drugs (aOR = 2.3, 95% CI = 1.3–4.1) in the past year; their mental health was “not good” for ≥1 day during the past month (aOR = 1.6, 95% CI = 1.2–2.2); their most recent CD4 count was <200 cells/μL (aOR = 1.6, 95% CI = 1.1–2.2); or taking ART usually (aOR = 9.6, 95% CI = 6.7–13.7) or sometimes/rarely/never (aOR = 18.4, 95% CI = 11.1–30.4), compared with always, as prescribed.

Conclusion/Significance

Providers should inquire about and promote strategies to improve adherence to PCP prophylaxis, particularly among persons who use illicit drugs, have mental health issues, and who are not compliant with ART to reduce the occurrence of PCP.

Bacterial infections are the most common cause for treatment-related mortality in patients with neutropenia after chemotherapy. Here, we discuss the use of antibacterial prophylaxis against bacteria and Pneumocystis pneumonia (PCP) in neutropenic cancer patients and offer guidance towards the choice of drug. A literature search was performed to screen all articles published between September 2000 and January 2012 on antibiotic prophylaxis in neutropenic cancer patients. The authors assembled original reports and meta-analysis from the literature and drew conclusions, which were discussed and approved in a consensus conference of the Infectious Disease Working Party of the German Society of Hematology and Oncology (AGIHO). Antibacterial prophylaxis has led to a reduction of febrile events and infections. A significant reduction of overall mortality could only be shown in a meta-analysis. Fluoroquinolones are preferred for antibacterial and trimethoprim–sulfamethoxazole for PCP prophylaxis. Due to serious concerns about an increase of resistant pathogens, only patients at high risk of severe infections should be considered for antibiotic prophylaxis. Risk factors of individual patients and local resistance patterns must be taken into account. Risk factors, choice of drug for antibacterial and PCP prophylaxis and concerns regarding the use of prophylactic antibiotics are discussed in the review.

OBJECTIVE--To assess the value of CD4 T cell count in predicting Pneumocystis carinii pneumonia in infants born to mothers infected with HIV, with reference to the guidelines from the Centers for Disease Control on prophylaxis against pneumocystis. DESIGN--Prospective birth cohort study. SETTING--Hospitals in 10 European cities participating in the European collaborative study. SUBJECTS--924 children born to mothers known to be infected with HIV at or before delivery. MAIN OUTCOME MEASURES--The incidence of P carinii pneumonia. CD4 T cell counts in children before diagnosis of the pneumonia. The proportions of children infected and uninfected with HIV who fulfilled the criteria for primary prophylaxis. RESULTS--Fourteen children were diagnosed with P carinii pneumonia. The cumulative incidence by the age of 6 years was 2% (95% confidence interval 0.9 to 3.0%). Of the 11 children with a CD4 T cell count predating diagnosis, only three fulfilled the criteria from the Centers for Disease Control for prophylaxis. Prophylaxis was indicated by 1 year of age for 62% of infected children who had not developed P carinii pneumonia and for at least 10% of uninfected children. CONCLUSIONS--Monitoring CD4 T cell count seems to be of limited value in deciding when to start prophylaxis against P carinii pneumonia in children born to mothers infected with HIV. The alternative approach of giving prophylaxis to all children born to infected mothers would be difficult to justify given the low incidence of the pneumonia.

Extrapulmonary pneumocystosis is an exceedingly rare complication of Pneumocystis carinii pneumonia (PCP). Prior to the advent of the human immunodeficiency virus type 1 (HIV-1) epidemic, only 16 cases of extrapulmonary pneumocystosis in individuals who were immunocompromised by a variety of underlying diseases had been reported. Since the beginning of the HIV-1 and related PCP epidemic, at least 90 cases of extrapulmonary pneumocystosis have been reported. This review briefly presents a history of the discovery of P. carinii and its recognition as a human pathogen, the controversy regarding its taxonomy, and the epidemiology of this organism. A more detailed analysis of the incidence of extrapulmonary pneumocystosis in HIV-1-infected individuals and its occurrence despite widespread prophylaxis for PCP with either aerosolized pentamidine or systemic dapsone-trimethoprim is presented. The clinical features of published cases of extrapulmonary pneumocystosis in non-HIV-1-infected individuals are summarized and contrasted with those in HIV-1 infected individuals. The diagnosis of extrapulmonary pneumocystosis is discussed, and because clinical microbiologists and pathologists are the key individuals in establishing the diagnosis, the characteristic microscopic morphology of P. carinii as its appears when stained with a variety of stains is presented and reviewed. The review concludes with a brief discussion of treatments for extrapulmonary pneumocystosis.

Meta-analysis shows increased risk for DHPS mutations in patients exposed to sulfa prophylaxis for PCP, but clinical relevance of mutations is not known.

A systematic review was conducted to examine the associations in Pneumocystis jirovecii pneumonia (PCP) patients between dihydropteroate synthase (DHPS) mutations and sulfa or sulfone (sulfa) prophylaxis and between DHPS mutations and sulfa treatment outcome. Selection criteria included study populations composed entirely of PCP patients and mutation or treatment outcome results for all patients, regardless of exposure status. Based on 13 studies, the risk of developing DHPS mutations is higher for PCP patients receiving sulfa prophylaxis than for PCP patients not receiving sulfa prophylaxis (p < 0.001). Results are too heterogeneous (p < 0.001) to warrant a single summary effect estimate. Estimated effects are weaker after 1996 and stronger in studies that included multiple isolates per patient. Five studies examined treatment outcome. The effect of DHPS mutations on treatment outcome has not been well studied, and the few studies that have been conducted are inconsistent even as to the presence or absence of an association.

Background

Pneumocystis pneumonia (PCP) is an increasing problem amongst patients on immunosuppression with autoimmune inflammatory disorders (AID). The disease presents acutely and its diagnosis requires bronchoalveolar lavage in most cases. Despite treatment with intravenous antibiotics, PCP carries a worse prognosis in AID patients than HIV positive patients. The overall incidence of PCP in patients with AID remains low, although patients with Wegener's granulomatosis are at particular risk.

Discussion

In adults with AID, the risk of PCP is related to treatment with systemic steroid, ill-defined individual variation in steroid sensitivity and CD4+ lymphocyte count. Rather than opting for PCP prophylaxis on the basis of disease or treatment with cyclophosphamide, we argue the case for carrying out CD4+ lymphocyte counts on selected patients as a means of identifying individuals who are most likely to benefit from PCP prophylaxis.

Summary

Corticosteroids, lymphopenia and a low CD4+ count in particular, have been identified as risk factors for the development of PCP in adults with AID. Trimethoprim-sulfamethoxazole (co-trimoxazole) is an effective prophylactic agent, but indications for its use remain ill-defined. Further prospective trials are required to validate our proposed prevention strategy.

Among the HIV-associated pulmonary complications, opportunistic pneumonias are major causes of morbidity and mortality. The spectrum of HIV-associated opportunistic pneumonias is broad and includes bacterial, mycobacterial, fungal, viral, and parasitic pneumonias. Bacterial pneumonia is the most frequent opportunistic pneumonia in the United States and Western Europe while tuberculosis (TB) is the dominant pathogen in sub-Saharan Africa. With the use of combination antiretroviral therapy and prophylaxis, the incidence of Pneumocystis pneumonia (PCP) has declined. Nevertheless, PCP continues to occur in persons who are unaware of their HIV infection, those who fail to access medical care, and those who fail to adhere to antiretroviral therapy or prophylaxis. Although pneumonias due to Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, cytomegalovirus (CMV), and Toxoplasma gondii are less frequent, their presence in the lung is often indicative of disseminated disease and is associated with significant mortality.

In developed countries, care and treatment are available for pregnant women and infants that can decrease the rate of perinatal human immunodeficiency virus type 1 (HIV-1) infection to 2% or less. The paediatrician has a key role in the prevention of mother-to-child transmission of HIV-1 by identifying HIV-exposed infants whose mothers’ HIV infection was not diagnosed before delivery, prescribing antiretroviral prophylaxis for these infants to decrease the risk of acquiring HIV-1 infection, and promoting avoidance of HIV-1 transmission through human milk. In addition, the paediatrician can provide care for HIV-exposed infants by monitoring them for early determination of HIV-1 infection status and for possible short- and long-term toxicities of antiretroviral exposure, providing chemoprophylaxis for Pneumocystis pneumonia, and supporting families living with HIV-1 infection by providing counselling to parents or caregivers.

Molecular evidence indicates that P. jirovecii may be nosocomially transmitted to severely immunosuppressed patients.

Ten Pneumocystis jirovecii pneumonia (PCP) cases were diagnosed in renal transplant recipients (RTRs) during a 3-year period. Nosocomial transmission from HIV-positive patients with PCP was suspected because these patients shared the same hospital building, were not isolated, and were receiving suboptimal anti-PCP prophylaxis or none. P. jirovecii organisms were typed with the multitarget polymerase chain reaction–single-strand conformation polymorphism method. Among the 45 patients with PCP hospitalized during the 3-year period, 8 RTRs and 6 HIV-infected patients may have encountered at least 1 patient with active PCP within the 3 months before the diagnosis of their own PCP episode. In six instances (five RTRs, one HIV-infected patient), the patients harbored the same P. jirovecii molecular type as that found in the encountered PCP patients. The data suggest that part of the PCP cases observed in this building, particularly those observed in RTRs, were related to nosocomial interhuman transmission.

OBJECTIVE

To examine the association of clinic HIV-focused features and advanced HIV care experience with Pneumocystis carinii pneumonia (PCP) prophylaxis and development of PCP as the initial AIDS diagnosis.

DESIGN

Nonconcurrent prospective study.

SETTING

New York State Medicaid Program.

PARTICIPANTS

Medicaid enrollees diagnosed with AIDS in 1990–1992.

MEASUREMENTS AND MAIN RESULTS

We collected patient clinical and health care data from Medicaid files, conducted telephone interviews of directors of 125 clinics serving as the usual source of care for study patients, and measured AIDS experience as the cumulative number of AIDS patients treated by the study clinics since 1986. Pneumocystis carinii pneumonia prophylaxis in the 6 months before AIDS diagnosis and PCP at AIDS diagnosis were the main outcome measures. Bivariate and multivariate analyses adjusted for clustering of patients within clinics. Of 1,876 HIV-infected persons, 44% had PCP prophylaxis and 38% had primary PCP. Persons on prophylaxis had 20% lower adjusted odds of developing PCP (95% confidence interval [CI] 0.64, 0.99). The adjusted odds of receiving prophylaxis rose monotonically with the number of HIV-focused features offered by the clinic, with threefold higher odds (95% CI 1.6, 5.7) for six versus two or fewer such features. Patients in clinics with three HIV-focused features had 36% lower adjusted odds of PCP than those in clinics with one or none. Neither clinic experience nor specialty had a significant association with prophylaxis or PCP.

CONCLUSIONS

PCP prevention in our study cohort appears to be more successful in clinics offering an array of HIV-focused features.

OBJECTIVE: To determine the uptake of medical interventions amongst women known to be HIV positive and in contact with service providers. SUBJECTS: 400 HIV positive women from 15 STD/HIV clinics in Britain and Ireland recruited to the MRC collaborative study of HIV infection in women between June 1992 and August 1994. METHODS: Data obtained prospectively through direct questioning of all women by a physician or research nurse and review of medical and laboratory records. Data recorded on standardised forms and analysed centrally. RESULTS: Nearly one quarter (24%) of women with an AIDS diagnosis had never received Pneumocystis carinii pneumonia prophylaxis, and 24% had never received any antiretroviral therapy. Fewer than two-thirds of black African women had had a chest radiograph. Only one woman had received Pneumovax and only 4% of women had ever taken part in a clinical trial. CONCLUSIONS: A substantial proportion of women with HIV infection did not receive interventions of proven benefit, and participation in clinical trials was very uncommon. The reasons for such poor uptake should be explored among both health care workers and women with HIV infection.

Summary

In July 2010, the World Health Organization (WHO) released new guidelines entitled, “Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants: Towards universal access.” Previewed in November 2009 in abridged form, the completed document highlights the key WHO recommendations for antiretroviral treatment (ART) and prophylaxis in pregnant women, and contains substantial changes from the 2006 guidelines. Of note, the new guidelines recommend ART for all pregnant women with a CD4 cell count (CD4) less than 350 cells/mm3, regardless of their clinical stage; includes tenofovir (TDF) as an acceptable alternative component of an ART regimen in pregnant and breastfeeding women; encourages initiation of both ART and antiretroviral (ARV) prophylaxis early in pregnancy; eliminates single-dose nevirapine (sdNVP) per se as a prophylaxis option; lists three-drug ARV prophylaxis as an option for women who do not need ART for their own health; and introduces extended daily infant nevirapine (ED-NVP) as a strategy for prevention of breast milk transmission of HIV. This article reviews these new recommendations and their rationale, and highlights key implications and challenges to their implementation in the Zambian context.

Once regarded as an AIDS-defining illness, Pneumocystis pneumonia (PcP) is nowadays prevailing in immunocompromised HIV-negative individuals such as patients receiving immunosuppressive therapies or affected by primary immunodeficiency. Moreover, Pneumocystis clinical spectrum is broadening to non-severely-immunocompromised subjects who could be colonized by the fungus while remaining asymptomatic for PcP, thus being able to transmit the infection by airborne route to susceptible hosts. Although the taxonomical position of the Pneumocystis genus has been clarified, several aspects of its life cycle remain elusive such as its mode of proliferation within the alveolus or its ploidy level. As no long-term culture model exists to grow Pneumocystis organisms in vitro, an option was to use a model of immunosuppressed rat infected with Pneumocystis carinii and sort life cycle stage fractions using a high-through-put cytometer. Subsequently, ploidy levels of the P. carinii trophic and cystic form fractions were measured by flow cytometry. In the cystic form, eight contents of DNA were measured thus strengthening the fact that each mature cyst contains eight haploid spores. Following release, each spore evolves into a trophic form. The majority of the trophic form fraction was haploid in our study. Some less abundant trophic forms displayed two contents of DNA indicating that they could undergo (i) mating/fusion leading to a diploid status or (ii) asexual mitotic division or (iii) both. Even less abundant trophic forms with four contents of DNA were suggestive of mitotic divisions occurring following mating in diploid trophic forms. Of interest, was the presence of trophic forms with three contents of DNA, an unusual finding that could be related to asymmetrical mitotic divisions occurring in other fungal species to create genetic diversity at lower energetic expenses than mating. Overall, ploidy data of P. carinii life cycle stages shed new light on the complexity of its modes of proliferation.

We review studies of dihydropteroate synthase gene mutations in Pneumocystis jirovecii and summarize the evidence for resistance to sulfamethoxazole and dapsone.

Pneumocystis pneumonia (PCP) remains a major cause of illness and death in HIV-infected persons. Sulfa drugs, trimethoprim-sulfamethoxazole (TMP-SMX) and dapsone are mainstays of PCP treatment and prophylaxis. While prophylaxis has reduced the incidence of PCP, its use has raised concerns about development of resistant organisms. The inability to culture human Pneumocystis, Pneumocystis jirovecii, in a standardized culture system prevents routine susceptibility testing and detection of drug resistance. In other microorganisms, sulfa drug resistance has resulted from specific point mutations in the dihydropteroate synthase (DHPS) gene. Similar mutations have been observed in P. jirovecii. Studies have consistently demonstrated a significant association between the use of sulfa drugs for PCP prophylaxis and DHPS gene mutations. Whether these mutations confer resistance to TMP-SMX or dapsone plus trimethoprim for PCP treatment remains unclear. We review studies of DHPS mutations in P. jirovecii and summarize the evidence for resistance to sulfamethoxazole and dapsone.

PURPOSE

AIDS continues to devastate urban communities, particularly among marginally-housed, ethnic minority, and drug-using populations. This study (1) describes access to comprehensive medical care, quality of HIV-related care, and attitudes regarding health among HIV-infected residents of single-room occupancy (SRO) hotels and (2) explores predictors of the use of pneumocystis carinii pneumonia (PCP) prophylaxis and highly-active antiretroviral therapy (HAART).

METHODS

We conducted a cross-sectional, community-based study of 69 Bronx SRO hotel residents during May 1998. Utilizing door-to-door recruitment, we administered a 41-item, anonymous questionnaire to assess participants' demographic characteristics, level of illness and health care utilization, use of HIV-related therapies, and perceptions of their own health and medical care.

RESULTS

Of respondents, 65% identified as African-American or Black, 22% as Puerto Rican, and 13% as White or Other. The median age was 42; 68% were male, and 38% were high school graduates. Most individuals were marginally-housed (median stay = 9 months). Almost all participants (96%) paid for medical services via Medicaid. Of the 93% with HIV infection, 44% had been hospitalized at least once in the past year, 72% reported a history of AIDS-defining opportunistic infections, and the median CD4 count was 214. Over two-thirds were actively using drugs and/or alcohol.

Among HIV-infected residents, 81% had seen a doctor in the last three months. However, only 67% felt they had a "regular" physician, and 48% felt their access to medical care was average to very poor. Among eligible HIV-infected persons, only 39% had taken HAART and 73% had taken PCP prophylaxis in the last week. Predictors for the use of HAART included absence of active cocaine and/or crack use (RR = 3.91; 95% CI 1.03–14.8; p < .03), use of PCP prophylaxis (RR = 5.69; 95% CI .85–38.1; p < .03) and the belief that HAART "can help people with AIDS" (RR = 1.75; 95% CI 1.28–2.44; p < .03). HAART use did not correlate with site or frequency of medical care or active alcohol or heroin use. Individuals with regular doctors were less likely to have visited an emergency room in the past 3 months (RR = .41; 95% CI .22–.76; p < .02) and more likely to be taking PCP prophylaxis (RR = 2.68; 95% CI 1.19–6.02; p < .008).

CONCLUSION

Despite relatively advanced disease in this population of marginally-housed HIV-infected persons, significant proportions do not have a regular primary care provider, are not taking HAART, and report sub-optimal quality of and access to medical care. Active cocaine and/or crack use correlate with a lesser use of HAART.

Pneumocystis carinii is an opportunistic fungal pathogen that causes P. carinii pneumonia (PCP) in the immunocompromised host. We investigated the role of antibody Fc-mediated function in passive prophylaxis against the development of PCP in SCID mice. By comparison of anti-mouse P. carinii immunoglobulin G1 monoclonal antibody (MAb) 4F11(G1) and its F(ab′)2 derivative in an intranasal immunoprophylaxis model, we determined that Fc-mediated function is required for maximum effect of this antibody. Comparison of efficacy of antibody prophylaxis in SCID mice depleted of complement to that in nondepleted mice demonstrated that complement fixation by MAb 4F11(G1) is also necessary for optimal effect of passively administered antibody, although residual protection was observed in complement-depleted SCID mice. The necessity of complement for optimal PCP prophylaxis by MAb 4F11(G1) suggests that complement may play a role in antibody-mediated protection against development of PCP.