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We describe a non-parametric multiple imputation method that recovers the missing potential censoring information from competing risks failure times for the analysis of cumulative incidence functions. The method can be applied in the settings of stratified analyses, time-varying covariates, weighted analysis of case-cohort samples and clustered survival data analysis, where no current available methods can be readily implemented. The method uses a Kaplan-Meier imputation method for the censoring times to form an imputed data set, so cumulative incidence can be analyzed using techniques and software developed for ordinary right censored survival data. We discuss the methodology and show from both simulations and real data examples that the method yields valid estimates and performs well. The method can be easily implemented via available software with a minor programming requirement (for the imputation step). It provides a practical, alternative analysis tool for otherwise complicated analyses of cumulative incidence of competing risks data.

Increasing numbers of patients are treated with mega-highly active antiretroviral therapy (HAART), or multiple-combination antiretroviral therapy, in an attempt to overcome the viral resistance that has contributed to treatment failure. Studies of human immunodeficiency virus (HIV) viral dynamics are used to quantify the potency of a given regimen. While mega-HAART is expected to provide potent therapy, its potency among heavily experienced HIV-infected children who have failed previous treatment is untested. HIV dynamics studies performed in children have provided minimal information on viral dynamics during mega-HAART. The present study estimates first- and second-phase viral dynamics in six children on mega-HAART, following failure of combination therapy. The first phase of viral decay was rapid, relative to rates reported in previous pediatric studies (median δ = 0.778 d − 1 , range = 0.583 to 1.088, half-life 1 [ t 1 1/2 ] = 0.894 d ), while the second phase revealed results similar to those of previous studies (median μ = 0.026 d − 1 , range = −0.005 to 0.206, t 2 1/2 = 9.316d). This indicates that mega-HAART can provide potent therapy among heavily experienced pediatric patients.

We performed a 24-week, placebo-controlled, comparative trial of hydroxyurea (HU) monotherapy, didanosine(ddI) monotherapy, and the combination of ddI plus HU administered as 1000 mg qd or 1500 mg qd in antiretroviral-naive and experienced subjects with CD4+ lymphocyte counts of 200-700 cells/mm3. Enrollment included 134 subjects. HU enhanced the antiviral activity of ddI by 1.0 log10 copies/ml after 8 weeks of therapy, with sustained responses over 24 weeks. HU alone over 4 weeks had no effect. Lamivudine resistance had little impact on antiretroviral activity when examined across treatment arms. Increases in absolute CD4+ T cell counts, but not CD4+ T cell percentages, were less in subjects who received HU compared to ddI monotherapy, and lymphoproliferative responses to antigenic and mitogenic stimuli were not altered. Subjects who received HU 1500 mg were more likely to experience dose-limiting hematological toxicities compared to those who received 1000 mg, without any additional antiviral benefit. HU may continue to have a role as a component of HIV therapy.

From a study of 71 HIV-1-infected patients receiving abacavir in combination with 1 of 5 different HIV-1 protease inhibitors (indinavir, ritonavir, saquinavir, nelfinavir, or amprenavir), we found that the baseline HIV-1 RNA levels were highly predictive of the viral decay rates. The baseline HIV-1 RNA levels were negatively correlated with the first phase viral decay rates (r = -0.77, P < 0.001) and positively correlated with the second phase viral decay rates (r = 0.68, P < 0.001). In addition, the first phase viral decay rate was positively correlated with CD4+ cell increases. No significant correlation was found between viral decay rates and longer term (24 weeks) virologic responses, and no difference in viral decay rates was found among the 5 study regimens. These data suggest that the potency of the 5 treatment regimens was similar and was not predictive of long-term virologic failure.

Background Combined administration of the human immunodeficiency virus protease inhibitor indinavir (800 mg every 8 hours) with the antimycobacterial rifabutin (300 mg daily) results in a significant decrease in indinavir concentrations with subsequent risk of treatment failure, as well as a significant increase in rifabutin concentrations with increased toxicity. Therefore this study was designed to evaluate alternative dosing regimens. Methods Eighteen healthy volunteers received 300 mg rifabutin daily alone for 14 days and then 1000 mg indinavir every 8 hours plus rifabutin at a reduced dose of 150 mg daily, given at 8 AM or noon in a randomized crossover sequence for 14 days. Ten human immunodeficiency virus-infected subjects received 800 mg indinavir every 8 hours for 14 days and then 1000 mg indinavir every 8 hours plus 150 mg rifabutin daily at 8 AM for 14 days. Twenty-four-hour pharmacokinetic sampling was performed at the end of each 14-day study period. Results Indinavir, 1000 mg every 8 hours, coadministered with 150 mg rifabutin daily produced an area under the concentration-time curve similar to that of 800 mg indinavir every 8 hours. The mean area under the concentration-time curve values of rifabutin and 25-desacetyl rifabutin, when 150 mg rifabutin every morning was coadministered simultaneously with 1000 mg indinavir every 8 hours, were 70% and 120% higher than with 300 mg rifabutin daily alone. Drug concentrations were not different when rifabutin and indinavir were administered simultaneously at 8 AM or staggered by 4 hours. Conclusions Increasing indinavir's dose to 1000 mg every 8 hours when coadministered with rifabutin at a reduced dose of 150 mg daily compensates for rifabutin induction of indinavir metabolism. Rifabutin concentrations were still higher than with rifabutin alone despite a 50% reduction of rifabutin dose, which is the current recommendation when these 2 drugs are combined. The clinical significance of the increase in rifabutin and 25-desacetyl rifabutin concentrations is not known. Clinical Pharmacology & Therapeutics (2003) 73, 159–169; doi: 10.1067/mcp.2003.3

To evaluate the efficacy, safety and tolerability of ritonavir-boosted tipranavir (TPV/r) in HIV-1-infected pediatric patients.Open-label randomized pediatric trial (1182.14/PACTG1051) comparing TPV/r at two doses including an optimized background regimen.HIV-1-infected patients (2-18 years) with plasma viral load 1500 copies/ml or more were randomized to TPV/r 290/115 or 375/150 mg/m twice-daily oral solution and optimized background regimen. Week 48 efficacy, safety and tolerability results were evaluated.Children (n = 115; 97% treatment experienced) were randomized to low or high dose therapy. Eighty-eight remained on-treatment through 48 weeks. Baseline characteristics were similar between dose groups. At study entry, half of the HIV-1 isolates were resistant to all protease inhibitors. At 48 weeks, 39.7% low-dose and 45.6% high-dose TPV/r recipients had viral load less than 400 copies/ml and 34.5 and 35.1%, respectively, achieved viral load less than 50 copies/ml. Vomiting, cough and diarrhea were the most frequent adverse events. Grade 3 alanine aminotransferase elevations were observed in 6.3% of patients. No grade 4 alanine aminotransferase or grade 3/4 aspartate aminotransferase elevations were reported.TPV/r achieved a sustained virologic response, showed a good safety profile and was well tolerated at either dose. In pediatric patients with high baseline resistance profiles, high-dose TPV/r tended to demonstrate a better sustained response.

Background Mannose-binding lectin (MBL) is part of the lectin pathway of complement activation against various pathogens; however, its role in innate immune responses against HIV-1 infection in children is unknown. Objective This study evaluated the effects of mannose-binding lectin-2 (MBL2) alleles on HIV-1 disease progression and central nervous system (CNS) impairment in children. Methods A cohort of 1037 HIV-1–infected children enrolled in Pediatrics AIDS Clinical Trial Group protocols P152 and P300 before the availability of effective antiretroviral therapy was genotyped for MBL2 and evaluated for disease progression. Results Children with the homozygous variant MBL2-O/O genotype were more likely to experience rapid disease progression and CNS impairment than those with the wild-type AA genotype. The effects were predominantly observed in children younger than 2 years. In unadjusted Cox proportional hazards models, children younger than 2 years with MBL2-O/O experienced more rapid disease progression ( O/O vs AA : relative hazard [RH], 1.54; 95% CI, 1.07-2.22; P = .02; O/O vs A/O : RH, 2.28; 95% CI, 1.09-4.79; P = .029). Similarly, children with MBL2-O/O were more likely to experience rapid progression to CNS impairment ( O/O vs A/A : RH, 2.78; 95% CI, 1.06-2.69, P = .027; O/O vs A/O : RH, 1.69; 95% CI, 1.07-7.21; P = .035). The effects remained significant after adjustment for CD4 + lymphocyte count, plasma HIV-1 RNA, and other genotypes. Conclusions MBL2-O/O genotypes, which result in lower expression of MBL, are associated with more rapid HIV-1–related disease progression, including CNS impairment, predominantly in children younger than 2 years. These data suggest that MBL2 variants are associated with altered HIV-1 disease progression, particularly in young children.

We develop a sensitivity analysis method for comparing treatment-specific distributions where the endpoint is progression-free survival (PFS). The censoring process may be informative due to selective patient withdrawal, which occurs whenever disease evaluation has been discontinued without progression being documented. The sensitivity analysis explores the effects of the dependence between patient withdrawal and progression time using a conditional probability model which incorporates a set of sensitivity parameters. We propose an EM algorithm for estimation of PFS under the model for dependence and construct log-rank-type score statistics from the estimated distributions. Bootstrap procedures are used to estimate the variance of the score statistic. We also extend the methodology to incorporate additional survival information, which may be available on the cases who were withdrawn. An Eastern Cooperative Oncology Group (ECOG) advanced lung cancer clinical trial (E1594) is used to illustrate the methodology.

Background Human immunodeficiency virus (HIV) infection in infancy features a persistently high viral load and elevated antiretroviral drug clearance rates, which pose significant therapeutic challenges to the clinician. Viral and cellular kinetic analyses performed in HIV-infected adults have yielded significant insights into the dynamic setting of this viral infection. Similar studies are needed in pediatric populations, in whom differing dynamics might translate into age-specific treatment approaches. Methods Viral and cellular kinetic analyses were performed using a nonlinear mixed-effects model in a cohort of 48 infants 1-24 months of age enrolled in a trial of ritonavir-based highly active antiretroviral therapy (HAART). Results Infected cell compartment kinetics were comparable with reported adult values, with no age-specific differences demonstrated--suggesting the ability to suppress viral replication in infants receiving HAART. Comparisons between 2 ritonavir dosing schedules revealed significant improvement in phase 1/2 decay constants in favor of the higher dose. A negative correlation was established between plasma RNA levels and phase 1 decay rates, which has worrisome implications for infant therapeutics given high infant pretreatment plasma virus levels. Conclusions Ritonavir-based HAART regimens in infancy result in HIV decay constants comparable to those reported in adults, without age-specific variability. Despite higher plasma HIV levels and CD4 lymphocyte counts in infancy, HAART can result in timely, effective control of viral replication.

In this paper, we examine a method for analyzing competing risks data where the failure type of interest is missing or incomplete, but where there is an intermediate event, and only patients who experience the intermediate event can die of the cause of interest. In some applications, a method called “log-rank subtraction” has been applied to these problems. There has been no systematic study of this methodology, though. We investigate the statistical properties of the method and further propose a modified method by including a weight function in the construction of the test statistic to correct for potential biases. A class of tests is then proposed for comparing the disease-specific mortality in the two groups. The tests are based on comparing the difference of weighted log-rank scores for the failure type of interest. We derive the asymptotic properties for the modified test procedure. Simulation studies indicate that the tests are unbiased and have reasonable power. The results are also illustrated with data from a breast cancer study.

We characterized the viral dynamics of human immunodeficiency virus (HIV) type 1–infected adolescents receiving highly active antiretroviral therapy regimens (lamivudine [3TC]/zidovudine [ZDV]/efavirenz [EFV] 3TC/ZDV/nelfinavir [NFV] or other regimens) and studied the relationship of viral dynamics with baseline factors and virological responses. Viral decay rates for 115 evaluable subjects were estimated from a viral dynamic model. Viral dynamics in HIV-1–infected individuals aged 12–22 years were similar to those of HIV- 1–infected adults and infants. Individuals who received 3TC/ZDV/EFV had a more rapid phase 1 viral decay rate than those who received 3TC/ZDV/NFV or other regimens. Phase 1 viral decay rates were positively correlated with baseline RNA levels and week 1 virus load reductions. Our findings indicate that the 3TC/ ZDV/EFV regimen may be more potent than 3TC/ZDV/NFV or other regimens and that early viral dynamics or week 1 virus load reduction measurements may be useful in evaluating the potency of antiretroviral regimens. (authors)