Resolution of organ dysfunction as a predictor of long-term survival in necrotizing soft tissue infections: Analysis of the AB103 Clinical Composite Endpoint Study in Necrotizing Soft Tissue Infections trial and a retrospective claims database-linked chart study.

BACKGROUND: Necrotizing soft tissue infections (NSTIs) are an acute surgical condition with high morbidity and mortality. Timely identification, resuscitation, and aggressive surgical management have significantly decreased inpatient mortality. However, reduced inpatient mortality has shifted the burden of disease to long-term mortality associated with persistent organ dysfunction. METHODS: We performed a combined analysis of NSTI patients from the AB103 Clinical Composite Endpoint Study in Necrotizing Soft Tissue Infections randomized-controlled interventional trial (ATB-202) and comprehensive administrative database (ATB-204) to determine the association of persistent organ dysfunction on inpatient and long-term outcomes. Persistent organ dysfunction was defined as a modified Sequential Organ Failure Assessment (mSOFA) score of 2 or greater at Day 14 (D14) after NSTI diagnosis, and resolution of organ dysfunction defined as mSOFA score of 1 or less. RESULTS: The analysis included 506 hospitalized NSTI patients requiring surgical debridement, including 247 from ATB-202, and 259 from ATB-204. In both study cohorts, age and comorbidity burden were higher in the D14 mSOFA ≥2 group. Patients with D14 mSOFA score of 1 or less had significantly lower 90-day mortality than those with mSOFA score of 2 or higher in both ATB-202 (2.4% vs. 21.5%; p < 0.001) and ATB-204 (6% vs. 16%: p = 0.008) studies. In addition, in an adjusted covariate analysis of the combined study data sets D14 mSOFA score of 1 or lesss was an independent predictor of lower 90-day mortality (odds ratio, 0.26; 95% confidence interval, 0.13-0.53; p = 0.001). In both studies, D14 mSOFA score of 1 or less was associated with more favorable discharge status and decreased resource utilization. CONCLUSION: For patients with NSTI undergoing surgical management, persistent organ dysfunction at 14 days, strongly predicts higher resource utilization, poor discharge disposition, and higher long-term mortality. Promoting the resolution of acute organ dysfunction after NSTI should be considered as a target for investigational therapies to improve long-term outcomes after NSTI. LEVEL OF EVIDENCE: Prognostic/epidemiology study, level III.

A Novel Immune Modulator for Patients With Necrotizing Soft Tissue Infections (NSTI): Results of a Multicenter, Phase 3 Randomized Controlled Trial of Reltecimod (AB 103).

BACKGROUND AND OBJECTIVE: Reltecimod, a CD 28 T-lymphocyte receptor mimetic, inhibits T-cell stimulation by an array of bacterial pathogens. A previous phase 2 trial demonstrated improved resolution of organ dysfunction after NSTI. We hypothesized that early administration of reltecimod would improve outcome in severe NSTI. METHODS: Randomized, double-blind, placebo-controlled trial of single dose reltecimod (0.5 mg/kg) administered within 6 hours of NSTI diagnosis at 65 of 93 study sites. Inclusion: surgical confirmation of NSTI and organ dysfunction [modified Sequential Organ Failure Assessment Score (mSOFA) score ≥3]. Primary analysis was modified Intent-to-Treat (mITT), responder analysis using a previously validated composite endpoint, necrotizing infection clinical composite endpoint, defined as: alive at day 28, ≤3 debridements, no amputation beyond first operation, and day 14 mSOFA ≤1 with ≥3 point reduction (organ dysfunction resolution). A prespecified, per protocol (PP) analysis excluded 17 patients with major protocol violations before unblinding. RESULTS: Two hundred ninety patients were enrolled, mITT (Reltecimod 142, Placebo 148): mean age 55 ±â€Š15 years, 60% male, 42.4% diabetic, 28.6% perineal infection, screening mSOFA mean 5.5 ±â€Š2.4. Twenty-eight-day mortality was 15% in both groups. mITT necrotizing infection clinical composite endpoint success was 48.6% reltecimod versus 39.9% placebo, P = 0.135 and PP was 54.3% reltecimod versus 40.3% placebo, P = 0.021. Resolution of organ dysfunction was 65.1% reltecimod versus 52.6% placebo, P = 0.041, mITT and 70.9% versus 53.4%, P = 0.005, PP. CONCLUSION: Early administration of reltecimod in severe NSTI resulted in a significant improvement in the primary composite endpoint in the PP population but not in the mITT population. Reltecimod was associated with improved resolution of organ dysfunction and hospital discharge status.

A randomized, open-label, dose-response study of losartan in hypertensive children.

BACKGROUND AND OBJECTIVES: Once-daily losartan reduces BP in a dose-dependent manner and is well tolerated in hypertensive children aged 6-16 years. This study assessed the dose-response relationship, safety, and tolerability of losartan in hypertensive children aged 6 months to 6 years. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a 12-week, randomized, open-label, dose-ranging study, with a 2-year extension. Patients were randomized to losartan at the following dosages: 0.1 mg/kg per day (low), 0.3 mg/kg per day (medium), or 0.7 mg/kg per day (high). Losartan was titrated to the next dose level (to a 1.4 mg/kg per day maximum dosage, not exceeding 100 mg/d, which was not one of the three original doses offered at randomization) at weeks 3, 6, and 9 for patients who did not attain their goal BP and were not taking the highest dose. Dose response was evaluated by analyzing the slope of change in sitting systolic BP (SBP; primary end point) and diastolic BP (DBP; secondary end point) after 3 weeks compared with baseline. Adverse events (AEs) were recorded throughout. RESULTS: Of the 101 patients randomized, 99 were included in the analysis (low dose, n=32; medium dose, n=34; and high dose, n=33). Mean sitting BP decreased from baseline in the low-, medium-, and high-dose groups by 7.3, 7.6, and 6.7 mmHg, respectively, for SBP and 8.2, 5.1, and 6.7 mmHg, respectively, for DBP after 3 weeks. No dose-response relationship was established by the slope analysis on SBP (P=0.75) or DBP (P=0.64). The BP-lowering effect was observed throughout the 2-year extension. The incidence of AEs was low and comparable between groups. CONCLUSIONS: Hypertensive children aged 6 months to 6 years treated with losartan 0.1-0.7 mg/kg per day had clinically significant decreases from baseline in SBP and DBP, yet no dose-response relationship was evident. Losartan, at a dosage up to 1.4 mg/kg per day, was well tolerated.

Declines in mortality rates and changes in causes of death in HIV-1-infected children during the HAART era.

CONTEXT: Introduction of highly active antiretroviral therapy has significantly decreased mortality in HIV-1-infected adults and children. Although an increase in non-HIV-related mortality has been noted in adults, data in children are limited. OBJECTIVES: To evaluate changes in causes and risk factors for death among HIV-1-infected children in Pediatric AIDS Clinical Trials Group 219/219C. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, prospective cohort study designed to evaluate long-term outcomes in HIV-1-exposed and infected US children. There were 3553 HIV-1-infected children enrolled and followed up between April 1993 and December 2006, with primary cause of mortality identified in the 298 observed deaths. MAIN OUTCOME MEASURES: Mortality rates per 100 child-years overall and by demographic factors; survival estimates by birth cohort; and hazard ratios for mortality by various demographic, health, and antiretroviral treatment factors were determined. RESULTS: Among 3553 HIV-1-infected children followed up for a median of 5.3 years, 298 deaths occurred. Death rates significantly decreased between 1994 and 2000, from 7.2 to 0.8 per 100 person-years, and remained relatively stable through 2006. After adjustment for other covariates, increased risk of death was identified for those with low CD4 and AIDS-defining illness at entry. Decreased risks of mortality were identified for later birth cohorts, and for time-dependent initiation of highly active antiretroviral therapy (hazard ratio 0.54, P < 0.001). The most common causes of death were "End-stage AIDS" (N = 48, 16%) and pneumonia (N = 41, 14%). The proportion of deaths due to opportunistic infections (OIs) declined from 37% in 1994-1996 to 24% after 2000. All OI mortality declined during the study period. However, a greater decline was noted for deaths due to Mycobacterium avium complex and cryptosporidium. Deaths from "End-stage AIDS," sepsis and renal failure increased. CONCLUSIONS: Overall death rates declined from 1993 to 2000 but have since stabilized at rates about 30 times higher than for the general US pediatric population. Deaths due to OIs have declined, but non-AIDS-defining infections and multiorgan failure remain major causes of mortality in HIV-1-infected children.

Virologic and immunologic correlates with the magnitude of antibody responses to the hepatitis A vaccine in HIV-infected children on highly active antiretroviral treatment.

BACKGROUND: HIV-infected individuals mount poor antibody responses to vaccines. We sought to identify the immunologic and virologic factors associated with a robust response to hepatitis A virus (HAV) vaccine in children on highly active antiretroviral treatment. METHODS: One hundred fifty-two pediatric highly active antiretroviral treatment recipients immunized against HAV at weeks 0 and 24 had anti-HAV antibodies, CD4+, CD8+, and CD19+ cell percent assessed at weeks 0 and 32. Subgroups had HIV viremia, B- and T-cell subpopulations, and cell-mediated immunity (CMI) to HAV and other stimulants measured. RESULTS: Anti-HAV antibodies after complete vaccination correlated positively with CD4+ percent and CD19+ percent and negatively with viremia and CD8+ percent at baseline, but not at 32 weeks. There were no significant correlations between anti-HAV antibodies and B- or T-cell-naïve, memory, or activated subpopulations or non-HAV CMI. Compared with children who remained HAV-CMI-negative, those who mounted HAV-CMI in response to vaccination had higher anti-HAV antibody titers and CD19+ CD21+ CD27+ memory B cell percent at 32 weeks, but no other differences. CONCLUSIONS: In HIV-infected children on highly active antiretroviral treatment, control of viral replication and conserved or reconstituted CD19+ and CD4+ cell numbers and function determine a robust antibody response to anti-HAV primary immunization. Our data support a bidirectional B- and T-cell cooperation in the response to the HAV vaccine.

Incidence of noninfectious conditions in perinatally HIV-infected children and adolescents in the HAART era.

OBJECTIVE: To estimate highly active antiretroviral therapy (HAART)-era incident rates for the first episode of noninfectious conditions in human immunodeficiency virus (HIV)-infected youth in order to identify HAART-era changes in the natural history of perinatal HIV infection. DESIGN: Multicenter prospective cohort study. SETTING: More than 80 sites in the United States including Puerto Rico. PATIENTS: Perinatally HIV-infected youth. MAIN OUTCOME MEASURES: Incidence rates (IRs) per 100 person-years were calculated for targeted noninfectious conditions occurring in perinatally HIV-infected children. A chi(2) test for linear trend was used to evaluate changes in the rates from 2001 to 2006. RESULTS: Two thousand five hundred seventy-five perinatally HIV-infected children (51%, female; 59%, black, non-Hispanic) were enrolled in Pediatric AIDS Clinical Trials Group (PACTG) 219C between 2000 and 2006 and were followed up for a median of 59 months. The 10 most common noninfectious conditions were pregnancy conditions (IR = 6.16; 95% confidence interval (CI), 3.9-9.3), birth defects (IR = 0.19; 95% CI, 0.1-0.3), gynecological dysplasias (IR = 5.92; 95% CI, 3.9-8.6), condyloma (IR = 0.15; 95% CI, 0.1-0.2), encephalopathy (IR = 0.38; 95% CI, 0.3-0.5), pancreatitis (IR = 0.30; 95% CI, 0.2-0.4), cardiac disorders (IR = 0.28; 95% CI, 0.2-0.4), renal disorders (IR = 0.26; 95% CI, 0.2-0.4), peripheral neuropathy (IR = 0.23; 95% CI, 0.2-0.4), and idiopathic thrombocytic purpura (IR = 0.15; 95% CI, 0.1-0.3). Among these conditions, 5 showed significant trends, with IRs increasing over time in pregnancy-related conditions (P < .001) and gynecological dysplasias (P = .02) while IRs decreased over time for encephalopathy (P < .001), pancreatitis (P = .002), and cardiac disorders (P = .007). CONCLUSIONS: Between 2001 and 2006, the incidence for 3 conditions decreased and increased for 2 others, demonstrating the change in medical issues and conditions in perinatally infected youth. Continued surveillance with appropriate tools will be needed to assess the long-term effects of HAART and HIV as well as development of new noninfectious conditions of HIV.

Simple Pediatric AIDS Severity Score (PASS): a pediatric severity score for resource-limited settings.

BACKGROUND: A multidimensional pediatric AIDS severity score (PASS) has been developed for severity adjustment and as a predictive model for mortality in a pediatric HIV-infected population. While the prognostic value of PASS is relevant in the US setting, there is a need to develop a simpler model of PASS for use in resource-limited settings where CD4% values and HIV RNA levels may not be available to assess prognosis and guide treatment decisions. METHODS: A Simple PASS model was developed including baseline weight percentile, WHO stage, symptoms, a general health rating, total lymphocyte count, packed-cell volume, and albumin measures from 1178 perinatally HIV-infected children enrolled into a prospective cohort study (PACTG 219). This prognostic model was then validated among 952 perinatally HIV-infected children enrolled in other PACTG research studies at the same sites. Survival estimates and Hazard Ratios (HR) were obtained using the Kaplan-Meier method and proportional hazards models, respectively. The predictive ability of the models was determined using Harrell's "C" statistic. RESULTS: Of the clinical measures and assays considered in this study, weight percentile, WHO stage, symptomatology, general health rating, total lymphocyte count, packed-cell volume, and albumin were found to be predictive of mortality. The simple PASS model including only the simple clinical measures and assays was found to be predictive of mortality (C statistic = 0.852). Its discriminative ability for mortality was comparable to a model consisting of the Simple PASS plus CD4% (C statistic = 0.871). CONCLUSION: The Simple PASS scoring system provides a reasonable alternative to CD4% values and HIV viral-load levels to assess prognosis and guide decisions about antiretroviral therapy initiation in resource-limited settings.

The Pediatric AIDS Severity Score (PASS): a multidimensional AIDS-severity adjustment for pediatric HIV infection.

BACKGROUND: A severity staging system predictive of mortality for perinatally HIV-infected children is needed for clinical and research purposes. METHODS: A pediatric AIDS severity score (PASS) was developed using baseline sociodemographic, clinical, immunologic, and functional measures obtained from 786 perinatally HIV-infected children enrolled into a prospective cohort study (PACTG 219) in the pre-highly active antiretroviral therapy (HAART) era (pre-1996). PASS was then validated among 392 perinatally HIV-infected children randomly sampled from the original source population (n = 1178). Survival estimates and hazard ratios (HRs) were obtained using the Kaplan-Meier method and proportional hazards models, respectively. The most predictive models were determined using Harrell's "C" statistic. RESULTS: Overall survival was 95% and 90% at 1 and 2 years of follow-up, respectively. The most comprehensive model for predicting mortality, termed the "Full" PASS, included CD4% <15 (HR = 3.9), CDC category C (HR = 2.6), BMI <10% (HR = 2.4), a low (<70) neuropsychological score (HR = 2.6), a general health rating <5 (HR = 2.4), and an elevated symptoms score (HR = 1.9). These determinants were highly predictive of mortality (C statistic = 0.841). CONCLUSIONS: PASS will be helpful in assessing the effectiveness of ART among children with HIV infection, particularly when randomized clinical trials are not possible due to ethical and feasibility concerns.

Incidence of opportunistic and other infections in HIV-infected children in the HAART era.

CONTEXT: Combination anti-retroviral therapy or highly active antiretroviral therapy (HAART) has resulted in a dramatic decline in the incidence of opportunistic and other infections in human immunodeficiency virus (HIV)-infected adults and children. OBJECTIVES: To estimate the incidence of 29 targeted opportunistic and other infections occurring in the era of HAART-between January 1, 2001, and December 31, 2004-in HIV-infected infants, children, and adolescents followed up in Pediatric AIDS Clinical Trials Group (PACTG) 219C; to compare incidence rates in the HAART era to those of the pre-HAART era; and to test for linear trends over time in the HAART era. DESIGN, SETTING, AND PARTICIPANTS: Ongoing, multicenter, prospective cohort study designed to examine long-term outcomes in HIV-infected children. The study population included 2767 children enrolled between September 15, 2000, and December 31, 2004, with information entered in the database up to August 1, 2005, when data analysis was conducted. The pre-HAART era comparison population included 3331 children enrolled in 13 PACTG protocols from October 1988 to August 1998. MAIN OUTCOME MEASURES: First occurrence of each of the 29 targeted infections. RESULTS: Seventy-five percent of the children were enrolled in 2000 and 2001, 90% acquired HIV perinatally, 52% were girls, and 59% were black. The median age was 8.2 years (range, 6-13 years). The median duration of follow-up was 3.4 years. Overall, 553 first episodes of a specific infection occurred among 395 (14%) of the study participants. The number of events for the 4 most common first-time infections and their incidence rates (IRs) per 100 person-years were 123 bacterial pneumonia (IR, 2.15; 95% confidence interval [CI], 1.79-2.56), 77 herpes zoster (IR, 1.11; 95% CI, 0.88-1.39), 57 dermatophyte infections (IR, 0.88; 0.67-1.14), and 52 oral candidiasis (IR, 0.93; 95% CI, 0.70-1.22). Incidence rates of first bacteremia, Pneumocystis jeroveci pneumonia, disseminated Mycobacterium avium complex, lymphoid interstitial pneumonitis, systemic fungal infection, cytomegalovirus retinitis, and tuberculosis were all less than 0.50 per 100 person-years. There were no statistically significant linear trends in incidence for any of the 29 infections over the 4 calendar years. However, infection rates were significantly lower than those reported in the PACTG in the pre-HAART era. The pre-HAART IRs were as follows: for bacterial pneumonia, IR, 11.1; 95% CI, 10.3-12.0; bacteremia, IR, 3.3; 95% CI, 2.9-3.8; herpes zoster, IR, 2.9; 95% CI, 2.6-3.3; disseminated M avium complex, IR, 1.8; 95% CI, 1.5-2.1; P jeroveci, IR, 1.3; 95% CI, 1.1-1.6; oral candidiasis, IR, 1.2; 95% CI, 1.0-1.5; cytomegalovirus retinitis, IR, 0.5; 95% CI, 0.3-0.6; and tuberculosis, IR, 0.2; 95% CI, 0.1-0.4. CONCLUSIONS: Opportunistic infections and other related infections are uncommon in children in the HAART era, and infection rates continue to be lower than those reported in the pre-HAART era. Continued surveillance is important to assess the long-term effect of HAART on the occurrence of opportunistic and other related infections in children.

Comparison of atovaquone and azithromycin with trimethoprim-sulfamethoxazole for the prevention of serious bacterial infections in children with HIV infection.

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMZ) has been used extensively for the prevention of Pneumocystis carinii (also referred to as "Pneumocystis jiroveci") pneumonia (PCP) and other opportunistic infections in human immunodeficiency virus (HIV)-infected children. Because the efficacy of TMP-SMZ for treatment of bacterial infections is limited, it is sometimes poorly tolerated, and there is risk of emergence of drug-resistant strains associated with widespread use, we evaluated a regimen that included atovaquone and azithromycin. METHODS: A randomized, double-blind, placebo-controlled trial was designed to determine whether atovaquone-azithromycin had equivalent efficacy to TMP-SMZ for the prevention of serious bacterial infections and to compare the long-term tolerance, PCP breakthrough rates, and nonserious bacterial infection rates among HIV-infected children aged 3 months to 19 years. Children qualified for PCP prophylaxis (on the basis of Centers for Disease Control and Prevention recommendations) were randomized to receive atovaquone-azithromycin or TMP-SMZ daily for >or=2 years. RESULTS: Data from 366 of the 369 eligible patients (median duration of follow-up, 3 years) showed that the estimated rates of serious bacterial infection-related events were lower among atovaquone-azithromycin recipients than among TMP-SMZ recipients (17.3 vs. 24.2 events per 100 patient-years; difference, 6.9 events per 100 patient-years; 95% confidence interval [CI], -0.22 to 14.12). Rates for all end points (serious bacterial infection, PCP, Mycobacterium avium complex infection, and serious and nonserious bacterial infection-related deaths) were 19.7 and 27.7 events per 100 patient-years, respectively (difference, 7.9 events per 100 patient-years; 95% CI, -0.28 to 15.54 events per 100 patient-years). The results marginally favored atovaquone-azithromycin therapy statistically. Atovaquone-azithromycin and TMP-SMZ therapies had similar adverse event profiles. CONCLUSIONS: We conclude that, in HIV-infected children, atovaquone-azithromycin is as effective as TMP-SMZ for the prevention of serious bacterial infections and is similarly tolerated.

Long-term effects of protease-inhibitor-based combination therapy on CD4 T-cell recovery in HIV-1-infected children and adolescents.

BACKGROUND: There is limited evidence about longer-term effects of combination antiretroviral therapy that includes protease inhibitors (PIs) on the immunological status of HIV-1-infected children. Better understanding might help to resolve questions on when to initiate treatment. METHODS: The change in percentage of CD4-positive T lymphocytes (CD4%) was investigated in 1012 previously treated HIV-1-infected children (aged 0-17 years) who were enrolled in research clinics in the USA before 1996 and followed up to 2000. 702 started PI-based combination therapy. Data analyses ignored subsequent treatment changes. FINDINGS: Among the 1012 children, the median CD4% increased from 22% to 28% between 1996, when PIs were first prescribed, and 2000. For the 702 who started PI-based therapy, the mean CD4% increase after 3 years was largest among participants with the greatest immunosuppression (15.7%, 10.6%, 5.1%, and 2.0% for participants with CD4% before therapy of <5%, 5-14%, 15-24%, and >25%; p<0.0001). After adjustment for pre-PI CD4%, the mean increase was largest among the youngest participants (9.2%, 8.0%, and 4.3% for ages <5 years, 5-9 years, and >10 years; p=0.001). However, only a minority of significantly immunocompromised participants (33%, 26%, and 49% of those with pre-PI CD4% of <5%, 5-14%, or 15-24%) achieved CD4% values above 25%, whereas 84% of those with pre-PI values above 25% maintained such values. INTERPRETATION: Although PI-based therapy was associated with substantial improvements in CD4%, initiation before severe immunosuppression and at younger ages may be more effective for recovery or maintenance of normal CD4%. Randomised investigation of when to start combination therapy in children, particularly infants, is needed.

Pharmacokinetics and tolerance of zidovudine in preterm infants.

OBJECTIVE: To determine zidovudine pharmacokinetics and tolerance in premature human human immunodeficiency virus-exposed infants. STUDY DESIGN: Pediatric AIDS Clinical Trials Group Study 331 was a multicentered prospective, open-label study of the use of zidovudine in premature infants. Thirty-eight infants <35 weeks' gestational age (GA) were studied while receiving zidovudine 1.5 mg/kg every 12 hours until 2 weeks of age, then 2.0 mg/kg every 8 hours until 6 weeks of age. Population pharmacokinetics were evaluated at 1, 2, and 4 weeks' postnatal age; zidovudine doses were adjusted to maintain troughs <3 microM. RESULTS: Zidovudine clearance was lower than reported in term infants at similar postnatal ages. Nine premature infants required dose reduction because of high levels (7/19 <30 weeks' and 2/19 >/=30 weeks' GA). Postnatal age, GA, serum creatinine, and furosemide use independently predicted zidovudine clearance. Zidovudine was generally well tolerated in this high-risk population. CONCLUSIONS: Zidovudine clearance is greatly reduced in premature infants. We recommend the following zidovudine dosing schedule in this population: 1.5 mg/kg (intravenous) or 2.0 mg/kg (oral) every 12 hours increased to every 8 hours at 2 weeks of age (>/=30 weeks' GA) or at 4 weeks (<30 weeks' GA).