Random-effects meta-analysis of inconsistent effects: a time for change.

A primary goal of meta-analysis is to improve the estimation of treatment effects by pooling results of similar studies. This article explains how the most widely used method for pooling heterogeneous studies--the Der Simonian-Laird (DL) estimator--can produce biased estimates with falsely high precision. A classic example is presented to show that use of the DL estimator can lead to erroneous conclusions. Particular problems with the DL estimator are discussed, and several alternative methods for summarizing heterogeneous evidence are presented. The authors support replacing universal use of the DL estimator with analyses based on a critical synthesis that recognizes the uncertainty in the evidence,focuses on describing and explaining the probable sources of variation in the evidence, and uses random-effects estimates that provide more accurate confidence limits than the DL estimator.

Long-term efficacy and safety of the HIV integrase inhibitor raltegravir in patients with limited treatment options in a Phase II study.

BACKGROUND: Raltegravir in combination therapy has demonstrated potent suppression of HIV-1 with a favorable safety profile. This report provides 96-week efficacy and safety data from Protocol 005, a Phase II study. METHODS: HIV-infected patients with very limited treatment options and failing antiretroviral therapy were randomized to raltegravir 200, 400, or 600 mg or placebo b.i.d., plus optimized background therapy for >or=24 weeks; all patients were then offered open-label raltegravir 400 mg b.i.d. Efficacy measurements included changes in viral load and CD4 count from baseline and percent of patients with HIV-1 RNA <400 and <50 copies/mL. RESULTS: One hundred and thirty-three patients received raltegravir and 45 received placebo. No dose-dependent differentiation in the safety or antiviral activity of raltegravir was observed during the double-blind phase. For the combined raltegravir groups, mean change in viral load from baseline was -1.60 log10 copies/mL at week 48 and -1.38 log10 copies/mL at week 96 (observed failure approach). At week 48, HIV-1 RNA levels were <400 copies/mL in 68% of raltegravir recipients and <50 copies/mL in 55%; these levels were maintained in 55% and 48% of raltegravir recipients, respectively, at week 96 (noncompleter = failure). There were few discontinuations of raltegravir (4%) due to adverse events. CONCLUSIONS: In patients with limited treatment options, raltegravir with OBT had a potent and sustained antiretroviral effect and was generally well tolerated through 96 weeks.

Introduction of ertapenem into a hospital formulary: effect on antimicrobial usage and improved in vitro susceptibility of Pseudomonas aeruginosa.

After ertapenem was added to the formulary of a 344-bed community teaching hospital, we retrospectively studied its effect on antimicrobial utilization and on the in vitro susceptibility of various antimicrobial agents against Pseudomonas aeruginosa. Three study periods were defined as preintroduction (months 1 to 9), postintroduction but before the autosubstitution of ertapenem for ampicillin-sulbactam (months 10 to 18), and after the policy of autosubstitution (months 19 to 48) was initiated. Ertapenem usage rose slowly from introduction to a range of 36 to 48 defined daily doses/1,000 patient days (DDD) with a resultant decrease in ampicillin-sulbactam usage due to autosubstitution. Imipenem usage peaked 6 months after the introduction of ertapenem and started to decline coincidently with the increased use of ertapenem. During the second period, imipenem usage decreased (slope = -1.28; P = 0.002). Prior to the introduction of ertapenem, the susceptibility of P. aeruginosa to imipenem increased from 61 to 81% at month 7 but then decreased slightly to 67% at month 9. After the introduction of ertapenem, susceptibility continued to increase; the increasing trend was significant (slope = 1.74; P < 0.001). In the third period, the median susceptibility (interquartile range) was 88% (82 to 95%). This change appeared related to decreased imipenem usage. For every unit decrease in the monthly DDD of imipenem, there was an increase of 0.38% (P = 0.008) in the susceptibility of P. aeruginosa to imipenem in the same month. Ertapenem was effective in our antimicrobial stewardship program and may have helped improve the P. aeruginosa antimicrobial susceptibility to imipenem by decreasing the unnecessary usage and selective pressure of antipseudomonal agents.

Raltegravir with optimized background therapy for resistant HIV-1 infection.

BACKGROUND: Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs. METHODS: We conducted two identical trials in different geographic regions to evaluate the safety and efficacy of raltegravir, as compared with placebo, in combination with optimized background therapy, in patients infected with HIV-1 that has triple-class drug resistance in whom antiretroviral therapy had failed. Patients were randomly assigned to raltegravir or placebo in a 2:1 ratio. RESULTS: In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups. CONCLUSIONS: In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection.

BACKGROUND: We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. METHODS: We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure. RESULTS: Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations. CONCLUSIONS: When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Efficacy, safety, and tolerability of long-term combination antiretroviral therapy in asymptomatic treatment-naïve adults with early HIV infection.

BACKGROUND: Initiating antiretroviral therapy in the early stages of HIV infection may afford benefits over delaying treatment. We evaluated the long-term efficacy and tolerrability of indinavir, zidovudine, and lamivudine begun in asymptomatic treatment-naïve adults with baseline CD4 counts 500 cells/mm3 and HIV (v)RNA levels >1000 copies/mL in an open-label, noncomparative study. METHOD: Proportions of participants with suppressed viremia were assessed using observed data, a model derived from generalized estimating equations counting only treatment-related discontinuations as failures (TRD=F), and a strict intention-to-treat analysis counting all noncompleters as failures (NC=F). RESULTS: 199 participants (median age 34; 79% men; 61% White) with a median CD4 count of 574 (range 130-1204) cells/mm3 and vRNA level of 3.89 (range 2.30-6.50) log10 copies/mL were followed up to 319 weeks. Overall, 142 participants (71%) discontinued the study after a median time of 112 weeks, including 4 (2%) due to unsuppressed viremia and 40 (20%) due to adverse events. After 156 weeks, 98%, 76%, and 53% of participants achieved <400 vRNA copies/mL based on observed data, TRD=F, and NC=F analyses, respectively; corresponding percentages <50 copies/mL were 93%, 72%, and 51%. Mean CD4 count increased by >250 cells/mm3 from baseline. Nausea (69%), fatigue (49%), diarrhea (37%), headache (28%), abdominal pain (28%), hematuria (27%), flank pain (26%), and hyperbilirubinemia (25%) were the most common drug-related adverse events. CONCLUSION: A minority of participants in this study completed follow-up. Despite durable HIV suppression in most participants remaining on treatment, treatment fatigue may interfere with long-term therapy in asymptomatic HIV-infected patients.

Impact of indinavir on the quality of life in patients with advanced HIV infection treated with zidovudine and lamivudine.

OBJECTIVE: In AIDS Clinical Trial Group (ACTG) study 320, triple-combination antiretroviral therapy including indinavir significantly slowed progression to acquired immunodeficiency syndrome or death, compared with treatment with dual nucleoside reverse-transcriptase inhibitors (NRTIs) alone, in zidovudine-experienced patients with advanced human immunodeficiency virus (HIV) infection. We examined the impact of indinavir on quality of life in participants from this study. METHODS: A total of 1156 protease inhibitor- and lamivudine-naive patients stratified by CD4 cell count (

Treatment of polymicrobial infections: post hoc analysis of three trials comparing ertapenem and piperacillin-tazobactam.

The efficacy of ertapenem 1 g once a day for the treatment of polymicrobial complicated intra-abdominal, complicated skin/skin-structure and acute pelvic infections was compared with piperacillin-tazobactam 3.375 g every 6 h in a post hoc analysis of data from three large randomized double-blind trials. Of the 1,558 treated patients in the three trials, no pathogen was identified in 345 (22.1%), 423 (27.2%) had a monomicrobial infection and 790 (50.7%) had a polymicrobial infection. At the test-of-cure assessment, there were no significant differences in outcome between the two treatment groups for any of the three infections. Cure rates (clinical and microbiological for intra-abdominal infection, clinical for skin/skin-structure and pelvic infections) in microbiologically evaluable patients for ertapenem and piperacillin-tazobactam, respectively, were 85.6% (154/180 evaluable patients) and 82.5% (127/154) for polymicrobial intra-abdominal infection, 80.3% (53/66) and 78.7% (48/61) for polymicrobial skin/skin-structure infection, and 95.7% (88/92) and 92.6% (88/95) for polymicrobial pelvic infection. Respective cure rates for all evaluable patients in the original trials were: 83.6% and 80.4% for intra-abdominal, 83.9% and 85.3% for skin/skin-structure, and 93.9% and 91.5% for pelvic infections. These data show that in the three trials, ertapenem 1 g once a day was highly effective for the treatment of polymicrobial infections and as effective as piperacillin-tazobactam 3.375 g every 6 h.