Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC-1 study.

BACKGROUND: Patients with relapsed/refractory multiple myeloma are at increased risk of infection. Infections during treatment with teclistamab, the first B-cell maturation antigen-directed bispecific antibody approved for triple-class-exposed relapsed/refractory multiple myeloma, was examined in the phase 1/2 MajesTEC-1 study. METHODS: Patients (N = 165) received subcutaneous teclistamab 1.5 mg/kg weekly after a step-up dosing schedule (0.06 mg/kg and 0.3 mg/kg, each separated by 2-4 days). Patients were monitored frequently for infections; prophylaxis and management were per institutional guidelines. RESULTS: At a median follow-up of 22.8 months (range, 0.3-33.6), infections were reported in 132 patients (80.0%). Grade 3/4 infections occurred in 91 patients (55.2%), including COVID-19 (21.2%), respiratory infections (19.4%), Pneumocystis jirovecii pneumonia (4.2%), viral infections (4.2%), and gastrointestinal infections (1.2%). Twenty-one patients died from infections (18 from COVID-19). Median time to first onset of any-grade and grade 3 to 5 infections was 1.7 and 4.2 months, respectively. Overall, 70.9% of patients had ≥1 postbaseline immunoglobulin G (IgG) level <400 mg/dL; median time to IgG <400 mg/dL was 1.2 months (range, 0.2-19.8) and 46.1% received ≥1 dose of IgG replacement. Grade 3/4 neutropenia occurred in 65.5% of patients (median time to grade ≥3 neutropenia/febrile neutropenia was 2.3 months [range, 0-18.1]). CONCLUSION: Based on the infection profile of B-cell maturation antigen-targeted bispecific antibodies such as teclistamab, it is recommended that clinicians and patients remain vigilant for a range of infection types throughout treatment to facilitate prompt intervention. Appropriate screening, prophylaxis, and management of infections, hypogammaglobulinemia, and neutropenia are important. CLINICAL TRIAL REGISTRATION: NCT03145181/NCT04557098 (ClinicalTrials.gov) PLAIN LANGUAGE SUMMARY: Before starting teclistamab, patients should be up to date with vaccinations (including COVID-19) and screened for hepatitis B and C and HIV. Teclistamab should not be given to patients with any active infections. Prophylactic antimicrobials should be administered per institutional guidelines. Prophylaxis for Pneumocystis jirovecii pneumonia and herpes simplex/varicella zoster virus is recommended during teclistamab treatment. Close monitoring of infections and immunoglobulin G (IgG) levels should continue throughout teclistamab treatment. IgG replacement (administered every 3-6 weeks) should be used to maintain IgG ≥400 mg/dL. Growth factors should be considered for grade ≥3 neutropenia with infection/fever and grade 4 neutropenia.

Cost-effectiveness analysis of diagnostic options for pneumocystis pneumonia (PCP).

BACKGROUND: Diagnosis of Pneumocystis jirovecii pneumonia (PCP) is challenging, particularly in developing countries. Highly sensitive diagnostic methods are costly, while less expensive methods often lack sensitivity or specificity. Cost-effectiveness comparisons of the various diagnostic options have not been presented. METHODS AND FINDINGS: We compared cost-effectiveness, as measured by cost per life-years gained and proportion of patients successfully diagnosed and treated, of 33 PCP diagnostic options, involving combinations of specimen collection methods [oral washes, induced and expectorated sputum, and bronchoalveolar lavage (BAL)] and laboratory diagnostic procedures [various staining procedures or polymerase chain reactions (PCR)], or clinical diagnosis with chest x-ray alone. Our analyses were conducted from the perspective of the government payer among ambulatory, HIV-infected patients with symptoms of pneumonia presenting to HIV clinics and hospitals in South Africa. Costing data were obtained from the National Institutes of Communicable Diseases in South Africa. At 50% disease prevalence, diagnostic procedures involving expectorated sputum with any PCR method, or induced sputum with nested or real-time PCR, were all highly cost-effective, successfully treating 77-90% of patients at $26-51 per life-year gained. Procedures using BAL specimens were significantly more expensive without added benefit, successfully treating 68-90% of patients at costs of $189-232 per life-year gained. A relatively cost-effective diagnostic procedure that did not require PCR was Toluidine Blue O staining of induced sputum ($25 per life-year gained, successfully treating 68% of patients). Diagnosis using chest x-rays alone resulted in successful treatment of 77% of patients, though cost-effectiveness was reduced ($109 per life-year gained) compared with several molecular diagnostic options. CONCLUSIONS: For diagnosis of PCP, use of PCR technologies, when combined with less-invasive patient specimens such as expectorated or induced sputum, represent more cost-effective options than any diagnostic procedure using BAL, or chest x-ray alone.

ß-d-Glucan kinetics for the assessment of treatment response in Pneumocystis jirovecii pneumonia.

Serum (1→3)-ß-D-Glucan (BG) is a biomarker for Pneumocystis jirovecii pneumonia (PJP). However, information concerning its usefulness for monitoring the clinical course is lacking. We conducted a retrospective study to investigate whether consecutive BG-measurements can be used to assess treatment response in PJP. Analysis of sera from 18 patients during PJP therapy shows that decreasing BG-levels strongly correlate with a favourable clinical course. In contrast, increasing BG-levels were associated with treatment failure or fatal outcome is only 44% of patients. As a consequence, BG-kinetics might be used to confirm treatment success but seem to be of limited value for the identification of treatment failure.

High rates of primary Mycobacterium avium complex and Pneumocystis jiroveci prophylaxis in the United States.

BACKGROUND: National data from the mid-1990s demonstrated that many eligible patients with HIV infection do not receive prophylaxis for opportunistic infections (OIs) and that racial and gender disparities existed in OI prophylaxis receipt. OBJECTIVE: We examined whether demographic disparities in use of OI prophylaxis persist in 2001 and if outpatient care is associated with OI prophylaxis utilization. RESEARCH DESIGN: Demographic, clinical, and pharmacy utilization data were collected from 10 U.S. HIV primary care sites in the HIV Research Network. SUBJECTS: This study consisted of adult patients (>or=18 years old) in longitudinal HIV primary care. MEASURES: Indications for Pneumocystis jiroveci pneumonia (PCP) or Mycobacterium avium complex (MAC) prophylaxis were 2 or more CD4 counts less than 200 or 50 cells/mm(3) during calendar year (CY) 2001, respectively. Using multivariate logistic regression, we examined demographic and clinical characteristics associated with receipt of PCP or MAC prophylaxis and the association of outpatient utilization with appropriate OI prophylaxis. RESULTS: Among eligible patients, 88.1% received PCP prophylaxis and 87.6% received MAC prophylaxis. Approximately 80% had 4 or more outpatient visits during CY 2001. Adjusting for care site, male gender (odds ratio [OR], 1.47), Medicare coverage (OR, 1.60), and having 4 or more outpatient visits in a year (OR, 2.34) were significantly associated with increased likelihood of PCP prophylaxis. Adjusting for care site, having 4 or more outpatient visits in a year (OR, 1.85) was associated with increased likelihood of receipt of MAC prophylaxis. There were no demographic or insurance characteristics associated with receipt of MAC prophylaxis. CONCLUSIONS: The overall prevalence of OI prophylaxis has increased since the mid-1990s, and previous racial and HIV risk factor disparities in receipt of OI prophylaxis have waned. Integration into the healthcare system is an important correlate of receiving OI prophylaxis.

Managed care for AIDS patients: is bigger better?

CONTEXT: Medicaid provides funds for the majority of AIDS-related health care services in the United States. In an effort to stabilize steeply rising Medicaid costs, managed care programs are replacing traditional fee-for-service Medicaid services. OBJECTIVE: To assess the impact of patient volume on the quality of care received by AIDS patients within a state's Medicaid managed care system. DESIGN: Cohort study of AIDS patients who were enrolled in Medicaid at any time from July 1997 through December 1998. Patient charts were reviewed and abstracted. Additional information on the AIDS patients' mode of exposure, date of AIDS diagnosis, and vital status were obtained from the state's HIV/AIDS surveillance database. PATIENTS AND SETTING: All known AIDS patients enrolled in the Maryland Medicaid managed care program were eligible. A total of 1052 of 1585 patient records were reviewed and analyzed. MAIN OUTCOME MEASURES: CD4 and viral load tests; preventive health care including screening for sexually transmitted infections; placement of tuberculin purified protein derivative (PPDs); hepatitis B and C screening; vaccination for hepatitis B; vaccination for pneumococcal pneumonia; Papanicolaou test screening; medication utilization including receipt of antiretroviral therapy and prophylaxis against Pneumocystis carinii pneumonia; case management services; and mortality. RESULTS: Health care quality indicators were examined by comparing the performance of clinical sites that saw a low volume of Medicaid AIDS patients per site (1-15 patients), a medium volume (16-100 patients), and a high volume (101-500 patients). High-volume sites performed better on virtually all quality indicators. There were few differences in performance between low- and medium-volume sites. High-volume sites experienced a greater number of patient deaths; this was true after adjusting for potential confounders such as age, use of antiretrovirals, time since AIDS diagnosis, appropriate laboratory monitoring, and hospitalizations. CONCLUSIONS: Variations in quality of care for AIDS patients were observed in a statewide managed care system. These variations existed despite provisions to ensure quality care such as an enhanced payment system for managed care organizations providing services for AIDS. High-volume sites were more likely to adhere to Public Health Service guidelines and may offer the best opportunity to provide high-quality AIDS care.

Induced sputum for diagnosing Pneumocystis carinii pneumonia in HIV patients: new data, new issues.

The complexity of bronchoalveolar lavage (BAL) has motivated the search for noninvasive methodology to retrieve specimens for detecting the presence of various pulmonary diseases. Induced sputum (IS) has been shown to be a reliable tool in terms of sensitivity and specificity comparable to BAL. Investigators from institutions worldwide have published several reports providing evidence in support of one or the other or a combination of both approaches. Among them are studies demonstrating the sensitivity and specificity of IS in diagnosing Pneumocystis carinii pneumonia (PCP) in patients with acquired immunodeficiency syndrome (AIDS). In 1996, highly active antiretroviral therapy was introduced for routine use and the morbidity from opportunistic infections decreased sharply. An earlier study showed that cost-effectiveness depends on the prevalence of a given condition in the population. More recent studies have confirmed that prophylaxis against PCP can be stopped after increasing the CD4 cell count, thus reducing the attractiveness of IS as a preferred method for monitoring the course of disease. This review presents a brief description of the evolution of the bronchoalveolar lavage versus induced sputum controversy and reconsiders the strengths and weaknesses of the earlier arguments in light of newer data that have emerged with regard to Pneumocystis carinii pneumonia in acquired immunodeficiency syndrome.

Comparing the survival of two groups with an intermediate clinical event.

Consider a subject entered on a clinical trial in which the major endpoint is a time metric such as death or time to reach a well defined event. During the observational period the subject may experience an intermediate clinical event. The intermediate clinical event may induce a change in the survival distribution. We consider models for the one and two sample problem. The model for the one sample problem enables one to test if the occurrence of the intermediate event changed the survival distribution. This models provides a way of carrying out non-randomized clinical trial to determine if a therapy has benefit. The two sample problem considers testing if the probability distributions, with and without an intermediate event, are the same. Statistical tests are derived using a semi-Markov or a time dependent mixture model. Simulation studies are carried out to compare these new procedures with the log rank, stratified log rank and landmark tests. The new tests appear to have uniformly greater power than these competitor tests. The methods are applied to a randomized clinical trial carried out by the Aids Clinical Trial Group (ACTG) which compared low versus high doses of zidovudine (AZT).

Should prophylaxis for Pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued?

Solid organ transplant recipients are at risk for Pneumocystis carinii pneumonia (PCP), but the risk of PCP beyond 1 year is poorly defined. We identified 25 cases of PCP in 1,299 patients undergoing solid organ transplantation between 1987 and 1996 at The Cleveland Clinic Foundation (4.8 cases per 1,000 person transplant-years [PTY]). Ten (36%) of 28 PCP cases (transplantation was performed before 1987 in three cases) occurred > or = 1 year after transplantation, and no patient developed PCP while receiving prophylaxis for PCP. The incidence of PCP during the first year following transplantation was eight times higher than that during subsequent years. The highest rate occurred among lung transplant recipients (22 cases per 1,000 PTY), for whom the incidence did not decline beyond the first year of transplantation. We conclude that the incidence of PCP is highest during the first year after transplantation and differs by type of solid organ transplant. Extending the duration of PCP prophylaxis beyond 1 year may be warranted for lung transplant recipients.

Clearance of Pneumocystis carinii cysts in acute P carinii pneumonia: assessment by serial sputum induction.

STUDY OBJECTIVES: To determine the feasibility of repeat sputum induction in acute Pneumocystis carinii pneumonia (PCP) and to define the rate of clearance of P carinii cysts from the respiratory tract of HIV-seropositive patients with acute PCP. DESIGN: Prospective cohort evaluation. SETTING: University medical center. PARTICIPANTS: Twenty-four HIV-seropositive subjects with acute PCP. MEASUREMENTS: Sputum induction for P carinii 2, 3, 4, and 6 weeks after initial diagnosis, and follow-up for 1 year. RESULTS: Eighty-eight percent of subjects had residual cysts at 2 weeks, 76% at 3 weeks, 29% at 4 weeks, and 24% at 6 weeks postdiagnosis. A prior AIDS-defining illness (p = 0.033) or prior PCP (p = 0.004) predicted relapse within 6 months, but persistent cysts at 3 weeks did not; 8 of 16 sputum-positive subjects and 1 of 5 sputum-negative subjects experienced a relapse within 6 months (p = 0.34). Secondary prophylaxis with trimethoprim-sulfamethoxazole was associated with a reduced risk of relapse. CONCLUSIONS: Serial sputum induction coupled with direct fluorescent antibody staining is a feasible, noninvasive method of respiratory tract surveillance for the eradication of P carinii during and after acute PCP. Three-quarters of HIV-seropositive patients with acute PCP have persistent cysts in their lungs at the end of antimicrobial treatment, despite clinical recuperation, but only one quarter have residual cysts 6 weeks postdiagnosis. A prior AIDS-defining illness and prior PCP are positively associated, and subsequent trimethoprim-sulfamethoxazole prophylaxis is negatively associated, with relapse within 6 months, while persistent organisms at 3 weeks do not appear to be a significant predictor of relapse risk.

Use of dapsone in the prevention and treatment of Pneumocystis carinii pneumonia: a review.

Dapsone, with or without trimethoprim or pyrimethamine, has strong anti-Pneumocystis carinii activity, as demonstrated by in vitro methods, animal studies, and clinical trials. The drug blocks folic acid synthesis of P. carinii by inhibition of dihydropteroate synthetase activity. Dapsone is efficiently absorbed (70%-80%) from the gastrointestinal tract, reaches peak serum concentration in 2-6 hours, and is adequately distributed to the fluid of the alveolar spaces. Synergistic effects against P. carinii are noted when trimethoprim is combined with dapsone. This combination is recommended for therapeutic use for P. carinii pneumonia (PCP) as an alternative for patients who cannot take trimethoprim-sulfamethoxazole (TMP-SMZ). Evidence from more than 40 studies of dapsone as prophylaxis for PCP in AIDS patients shows that dapsone, either alone or in combination with pyrimethamine, is as effective as aerosolized pentamidine or atovaquone but slightly less effective than TMP-SMZ. Adverse effects include rash, anemia, methemoglobinemia, agranulocytosis, and hepatic dysfunction. Desensitization can be accomplished with many cases. Dapsone is the most cost-effective prophylaxis currently available for PCP.

The safety of i.v. pentamidine administered in an ambulatory setting.

I.v. pentamidine is well known to cause severe multiorgan adverse effects and is usually given to hospitalized patients under close monitoring. The primary purpose of this retrospective quality assurance study is to assess the safety of administering i.v. pentamidine in the medical daycare unit (MDCU) for outpatients. Thirty-five outpatients infected with the HIV made 306 visits to the MDCU from January 1991 to December 1993. They received i.v. pentamidine in a dosage of either 300 mg once a month for prophylaxis or 4 mg/kg/d 5 days a week for treatment of Pneumocystis carinii pneumonia (PCP). BP was monitored every 15 to 30 min over 3 to 4 h and clinical side effects were noted. CBC count, BUN, creatinine, amylase, and blood glucose values were taken twice a week. The records were reviewed retrospectively and analyzed for clinical and biochemical derangement. GI side effects occurred in 59 of 306 (19%) visits; 43 (73%) of the side effects were nausea. Routine normal saline solution boluses before and after pentamidine infusion prevented the drop in BP and actually significantly elevated BP after i.v. pentamidine. The most common biochemical derangement was elevated BUN level in eight patients and creatinine in nine patients, but they were mild and required no intervention. Significant neutropenia occurred in three, anemia in two, hyponatremia in two, hyperamylasemia in two, and hyperglycemia in two patients. No palpitation or irregular pulse was encountered. No death was associated with the administration of i.v. pentamidine. Three patients required hospital admission. Only one hospital admission was definitely related to adverse drug effects. In conclusion, the side effects of i.v. pentamidine are common but minor. We conclude that it is safe to administer i.v. pentamidine in carefully selected patients with appropriate monitoring in an ambulatory setting. This has a major health economic implication, because ambulatory i.v. pentamidine can result in significant cost savings and can also enhance quality of life. Further studies regarding the feasibility of home administration of i.v. pentamidine is warranted as even further cost savings and improvement in the quality of life of HIV-infected patients may be achieved.

Pharmacoeconomics of Pneumocystis carinii pneumonia in HIV-infected and HIV-noninfected patients.

Despite the proven effectiveness of Pneumocystis carinii pneumonia (PCP) prophylaxis in both HIV-infected and HIV-noninfected patients, PCP remains an important cause of serious pulmonary infection. Because PCP is a frequent event requiring inpatient admission at our institution, we conducted a study to define the pharmacoeconomics of this infection and the incidence of adverse events associated with anti-PCP therapy. In a retrospective review, 133 patients (101 HIV-positive, 32 HIV-negative) with documented PCP were identified. Significant differences in age, initial arterial oxygen tension (paO2), intensive care unit admission and mortality were evident between HIV-infected and non-HIV-infected patients; however, there were no differences in the duration of hospitalisation or the duration of anti-PCP therapy. The incidence of biochemical abnormalities was similar between the groups. Leucopenia occurred at an incidence of 52 and 31%, while thrombocytopenia occurred at a rate of 7 and 44%, in HIV-positive and HIV-negative patients, respectively. Drug toxicity or treatment failure necessitated a change of therapy in 43% of HIV-positive and 59% of HIV-negative patients. PCP treatment cost, pharmacy cost, hospital cost and net loss (i.e. the difference between hospital cost and reimbursement) were all significantly greater in HIV-negative than in HIV-positive patients. The duration of anti-PCP therapy and the hospital cost for cotrimoxazole (trimethoprim-sulfamethoxazole)- and pentamidine-treated patients were similar, although the treatment cost and pharmacy cost were statistically different in favour of cotrimoxazole. Overall, cotrimoxazole is an inexpensive treatment option. However, the high incidence of adverse events attributed to this agent often necessitates a change to a more costly therapy.

Estimating the cost effectiveness of atovaquone versus intravenous pentamidine in the treatment of mild-to-moderate Pneumocystis carinii pneumonia.

Pneumocystis carinii pneumonia (PCP) is the most common severe opportunistic infection, and one of the most costly, among people with AIDS. Over 50% of patients experience toxic effects of the major anti-PCP medications- cotrimoxazole (trimethoprim-sulfamethoxazole) and pentamidine. Recently, the US Food and Drug Administration approved a new oral drug therapy, atovaquone, as an alternative to pentamidine for the treatment of people with mild-to-moderate PCP who are intolerant of cotrimoxazole. We developed a decision tree model to estimate the costs and cost effectiveness of atovaquone therapy compared with intravenous pentamidine therapy for cotrimoxazole-intolerant patients with mild-to-moderate PCP. Clinical outcomes were based on data from a phase III trial comparing the 2 medications. Our economic outcomes were based on treatment algorithms derived from discharge data, published reports and the clinical judgement of the co-authors. We estimate the total expected cost of treating a patient for an episode of PCP with atovaquone to be $US3990 compared with $US6545 for pentamidine under our baseline scenario (1995 dollars). Our decision model also provides insight into the large cost-savings benefits of treating mild-to-moderate PCP on an outpatient basis.

Inpatient treatment patterns of human immunodeficiency virus-associated Pneumocystis carinii pneumonia in New York State Medicare patients.

Hospital charts were reviewed to ascertain the frequency with which patients with human immunodeficiency virus (HIV)-associated Pneumocystis carinii pneumonia (PCP) were being managed in accordance with current guidelines or recommendations in New York State for the calendar year 1993. Comparisons were made between hospitals that are designated by the New York State Department of Health as comprehensive treatment centers--designated acquired immunodeficiency syndrome (AIDS) centers--and all other hospitals. For patients who had been on PCP prophylaxis before admission, 34% had documentation of positive histologic evidence for PCP infection during the studied hospitalization period. Of all patients not on PCP prophylaxis at the time of admission, 94% had at least one of the diagnostic tests for PCP done during the PCP hospitalization. Eighty-one percent of all patients had either pulse oximetry or an arterial blood gas determination. Seventy-seven percent of all patients with a PO2 equal to or less than 70 mm Hg received steroids. All eligible patients received one of nine possible treatment combinations, which included either single drug therapy, multiple drug therapy, or participation in a clinical trial. Sixteen percent of eligible patients had no documentation of receiving PCP medication at discharge. Proportions receiving diagnostic or treatment interventions were usually higher in designated AIDS centers than in non-designated AIDS centers.

Pneumocystis pneumonia in a prepaid care system caring for a Medicaid-covered population with AIDS.

Pneumocystis pneumonia (PCP) is the most common pneumonia in persons with acquired immunodeficiency syndrome (AIDS) and a frequent cause of hospitalization. The incidence of PCP in patients with AIDS can be substantially reduced when patients comply with standard prophylaxis protocols. However, achieving acceptable prophylaxis compliance in any patient population is difficult, particularly with intravenous drug users (IVDU), homeless, or medically disenfranchised patients. This study defines the rates and locations of treatment of PCP in a prepaid managed care program for a Medicaid-covered population with AIDS, with comparisons to PCP incidence rates in the same population receiving care in the fee-for-service system.