Short Course Of Therapy Research Articles

The Impact of Different Antibiotic Regimens on the Emergence of Antimicrobial-Resistant Bacteria

BackgroudThe emergence and ongoing spread of antimicrobial-resistant bacteria is a major public health threat. Infections caused by antimicrobial-resistant bacteria are associated with substantially higher rates of morbidity and mortality compared to infections caused by antimicrobial-susceptible bacteria. The emergence and spread of these bacteria is complex and requires incorporating numerous interrelated factors which clinical studies cannot adequately address.Methods/Principal FindingsA model is created which incorporates several key factors contributing to the emergence and spread of resistant bacteria including the effects of the immune system, acquisition of resistance genes and antimicrobial exposure. The model identifies key strategies which would limit the emergence of antimicrobial-resistant bacterial strains. Specifically, the simulations show that early initiation of antimicrobial therapy and combination therapy with two antibiotics prevents the emergence of resistant bacteria, whereas shorter courses of therapy and sequential administration of antibiotics promote the emergence of resistant strains.Conclusions/SignificanceThe principal findings suggest that (i) shorter lengths of antibiotic therapy and early interruption of antibiotic therapy provide an advantage for the resistant strains, (ii) combination therapy with two antibiotics prevents the emergence of resistance strains in contrast to sequential antibiotic therapy, and (iii) early initiation of antibiotics is among the most important factors preventing the emergence of resistant strains. These findings provide new insights into strategies aimed at optimizing the administration of antimicrobials for the treatment of infections and the prevention of the emergence of antimicrobial resistance.

Optimal duration of the antimicrobial treatment of ventilator-acquired pneumonia

The optimal duration of antimicrobial treatment of patients with ventilator-associated pneumonia is a major concern for clinicians. We looked for the evidence that a short course of therapy (≤10 days) is as effective as a traditional long-course therapy (14–21 days). Unfortunately, only one trial (PneumA trial) has focused directly on this question. To further evaluate this issue, we identified trials in which the duration of anti-infective treatment was used as the outcome. Such trials, by providing data on mortality, length of intensive care unit stay and recurrence, may allow for estimating the association between duration of therapy and the aforementioned outcomes. Nine such trials were identified; all reported a decrease in the total length of antibiotic administration (statistically significant in seven) with the application of the intervention studied. Short, as opposed to long, courses of antibiotics did not adversely affect mortality, length of intensive care unit stay or recurrence rates. In conclusion, the available evidence seems to support the use of short-course antimicrobial treatments (≤10 days) for patients with ventilator-acquired pneumonia not caused by nonfermenting Gram-negative bacilli.

Costimulation Blockade of CD40 and CD28 Pathways in Limb Transplantation

Costimulation blockade remains a promising experimental regimen for the induction of transplantation tolerance. The simultaneous blockade of both the CD40 and CD28 pathways has been synergistic in prolonging organ allograft survival but has not previously been investigated in a model of limb allotransplantation. This study determined the efficacy of this combination in the murine limb allograft model. C57B1/6 (H-2K b) female mice were recipients of heterotopic vascularized limb allografts from Balb/c (H-2K d) male donors. Experimental groups received treatment with a short course of MR1 (hamster anti-mouse anti-CD40 ligand antibody) alone or in combination with CTLA4-Ig, a fusion protein that blocks the B7/CD28 pathway. Untreated recipients rejected limb allografts at a mean of 9.6 ± 1.1 (standard error of the mean) days postoperatively. Recipients of a prolonged course of MR1 rejected limb allografts at 75 ± 25 days. When both MR1 and CTLA4-Ig were used, limb allograft survival of >120 days was observed despite a much shorter course of therapy. Rejection in both treatment groups was consistent with a chronic antibody-mediated process. Donor antigen rechallenge in these recipients by in vitro assay and skin allograft demonstrated a hyperacute response consistent with presensitization. Long-term limb allograft survival is produced by the synergistic effect of blocking both the CD40 and CD28 costimulatory pathways. However, permanent acceptance was not achieved, and allografts eventually succumbed to what appeared to be antibody-mediated rejection. The additional use of newer agents that block more recently described costimulatory pathways may be essential for the induction of tolerance by costimulation blockade.

Epiregulin as a key molecule to suppress hepatitis B virus propagation in vitro

Hepatitis B virus (HBV) infection is a major health concern around the world, and only a minority of patients receiving current treatments achieve a sustained response following a short course of therapy. The majority of patients require prolonged therapy to suppress viral replication. However, several recent reports show that inhibiting host-cell proteins can prevent viral infection. Human epiregulin (EREG) was confirmed by our previous study to be up-regulated in HepG2.2.15 cells while down-regulated by lamivudine. Therefore, the question was asked whether inhibiting EREG could prevent viral infection. To address this question, antisense oligonucleiotides (ASODNs) were used to down-regulate EREG expression in HepG2.2.15 cells. We were able to show that HBV propagation in HepG2.2.15 cell culture was reduced in a dose-dependent manner by EREG inhibition. In addition, we found that treatment with ASODNs did not affect HepG2.2.15 cell viability. To probe the role of EREG in HBV replication, the interaction between EREG and HBsAg was also verified using co-immunoprecipitation and GST pull-down assays. We observed that EREG can contribute to HBsAg binding to HepG2 cells. In summary, this study demonstrates that EREG is essential for HBV replication and also provides some evidence for the potential role of EREG in HBsAg binding.

Combination antifungal therapy: From bench to bedside

Invasive fungal infections are major causes of mortality in immunocompromised patients. Despite improved outcomes with new antifungals, there remains a pressing need to further improve outcomes, especially with invasive aspergillosis and other invasive mold infections. Combination antifungal therapy is an attractive option that offers the prospect for improved efficacy, decreased toxicity, reduced likelihood for the emergence of resistance, and shorter courses of therapy. The current available evidence regarding the role of combination antifungal therapy for invasive fungal infections is discussed in this article, including data from in vitro studies, animal models, and human clinical trials to try to clarify this important issue. Randomized, prospective clinical trials are urgently needed, especially for invasive aspergillosis.

Ovarian hyperstimulation after a short course of an oral contraceptive in a patient with premature ovarian failure

To report a patient with premature ovarian failure who, after discontinuing a short course of therapy with an oral contraceptive, demonstrated clinical and biochemical evidence of ovarian hyperstimulation. Case report. Reproductive Center at a university hospital. 31-year-old woman with premature ovarian failure. Triggered ovulation using recombinant human chorionic gonadotropin (hCG). Follicle sizes documented by transvaginal ultrasound and corresponding serum estradiol levels. Hyperstimulated ovaries, documented by pelvic ultrasound, demonstrated lead follicles of 16, 22, 27, and 46 mm in average diameters. The serum estradiol level was 979 pg/mL with a serum progesterone of 0.87 ng/mL. Five days after triggered ovulation with recombinant hCG, serum progesterone levels rose to 13.8 ng/mL. Ovarian hyperstimulation may occur after brief gonadotropin suppression in women with premature ovarian failure.

Combination antifungal therapy: From bench to bedside

Invasive fungal infections are major causes of mortality in immunocompromised patients. Despite improved outcomes with new antifungals, there remains a pressing need to further improve outcomes, especially with invasive aspergillosis and other invasive mold infections. Combination antifungal therapy is an attractive option that offers the prospect for improved efficacy, decreased toxicity, reduced likelihood for the emergence of resistance, and shorter courses of therapy. The current available evidence regarding the role of combination antifungal therapy for invasive fungal infections is discussed in this article, including data from in vitro studies, animal models, and human clinical trials to try to clarify this important issue. Randomized, prospective clinical trials are urgently needed, especially for invasive aspergillosis.

Cost minimisation analysis of 12 or 24 weeks of peginterferon alfa-2b + ribavirin for hepatitis C virus

Background: Pegylated interferon and ribavirin are at present the standard treatment for chronic hepatitis C virus (HCV) patients.Objective: The present economic evaluation compared 12 vs. 24 weeks of peginterferon alfa-2b + ribavirin treatments for HCV genotypes 2 or 3. Shortening the period of antiviral therapy is important in terms of adverse events and costs.Methods: Clinical evidence was based on the results of a multicentre, randomised controlled clinical trial (RCCT) conducted in Italy, which found that the shorter course of therapy was as effective as the 24-week course for patients with HCV genotypes 2 or 3 responding to treatment at 4 weeks. A cost minimisation analysis was performed. The analysis took the Italian National Health Service (INHS) point of view, thus only healthcare costs (drugs, medical consultations, diagnostic tests, hospital admissions) were considered. Healthcare activities were estimated by the RCCT principal investigators and were priced by applying the INHS tariffs and prices.Results: The total mean cost per patient was estimated at €9,785 for the standard group and €7,508 for the variable-duration group. Sensitivity analysis confirmed the robustness of the baseline results.Conclusions: This study showed that the variable-duration regimen can be recommended as an efficient use of resources for patients from the INHS perspective.

Helicobacter pylori: testing and treatment

Helicobacter pylori is an important pathogen worldwide. Accurate diagnosis and appropriate therapy is important in clinical practice. Invasive tests that accurately identify current infection include the biopsy urease test and histology. The best noninvasive tests for diagnosis include the urea breath test and stool antigen testing. Proton pump inhibitor therapy can lead to false-negative H. pylori test results, and treatment should be stopped for 1–2 weeks prior to testing if possible. In the setting of bleeding peptic ulcer disease, urea breath testing is recommended to rule out a false-negative biopsy test result if needed. The current recommendations for when to test for H. pylori vary around the world. Well-accepted indications include active and past ulcer disease, and gastric-mucosa associated lymphoid tissue lymphoma. There is no universal agreement regarding whether all patients with functional dyspepsia should be tested and treated, although this is an evidence-based recommendation. There is also evidence that H. pylori eradication prevents peptic ulcer disease in those starting NSAIDs long term. Primary treatment remains triple therapy with 10–14 days probably being superior to shorter courses of therapy. Quadruple therapy is recommended if standard triple therapy fails. Salvage therapies with levofloxacin, rifabutin or furazolidone have been identified. Novel approaches to treatment include sequential therapy and use of adjuvants.

Amiodarone-related Pneumonitis

Amiodarone-related pneumonitis is a potentially limiting factor for amiodarone usage. However, it is believed that amiodarone-related pneumonitis is unlikely to occur during low-dose and short courses of therapy. We report three patients who received low-dose amiodarone, 200 mg/day, for an average of 6.6 months and who developed amiodarone-related pneumonitis. All patients were male with age of 75, 93 and 85, respectively, and had the habit of cigarette smoking. The initial presentation was dyspnea without symptoms and signs of heart failure. Their chest radiographs showed diffuse interstitial pneumonitis pattern and chest computed tomography scan also confirmed interstitial pneumonitis. Treatment included cessation of amiodarone and corticosteroid usage. All patients improved symptomatically by early detection and early treatment. This case report implies that old age and possible pre-existing pulmonary abnormalities caused by smoking could be associated with amiodarone-related pulmonary toxicity. Clinicians must remain alert to detect amiodarone-related pneumonitis even under low dosage and short duration of amiodarone usage. Immediate withdrawal of amiodarone and prompt steroid therapy will ensure full recovery.

Outcome of treatment for congenital toxoplasmosis, 1981-2004: The national collaborative Chicago-based, congenital toxoplasmosis study

This is a report of a major national study reviewing long-term outcomes of 120 infants with congenital toxoplasmosis. Without treatment, toxoplasmosis is known to be a recurrent disease with many adverse outcomes, with regards to both neurologic status and specific organ systems. Even asymptomatic children who have congenital toxoplasmosis will go on to develop manifestations of clinical disease, including retinal lesions, later in life. Because of incomplete data regarding the prevalence of the disease or the effect of treatment, many aspects of the surveillance and management of congenital toxoplasmosis remain controversial. While it is currently standard practice to treat affected children with pyrimethamine and sulfadiazine for 1 year, the long-term effect is largely unknown. Since withholding treatment was considered unethical, this study compared children treated with two different regimens of pyrimethamine and sulfadiazine supplemented with folinic acid for 1 year. The authors then compared their outcomes with prior studies involving untreated children or children who received a short course of therapy (eg, 1 month). Compared with historical controls, patients who received a full year of therapy (either dosage) had markedly improved cognitive outcome, neurologic function, and specifically, visual outcomes. Ninety-one percent of children without evidence of important neurologic impairment and 64% with moderate-to-severe impairment at birth did not develop new eye lesions. In the neurologically intact group, only 2 of 13 (15%) patients were considered visually impaired at their final examination, as opposed to 47 of 55 (85%) in the more severely affected group (p < 0.001). This important national study reminds us that visual impairment is one of the important sequelae of congenital toxoplasmosis, which may be missed during routine well-child examinations. Such children, if discovered by the ophthalmologist, should be referred for formal examination and treatment. Because of the effectiveness of intervention, routine prenatal or neonatal serologic screening may be warranted.

Once-a-day Amoxicillin Therapy of Streptococcal Pharyngitis: Good, Better and, Future, Best?

Source: Clegg HW, Ryan AG, Dallas SD, et al. Treatment of streptococcal pharyngitis with once-daily compared with twice-daily amoxicillin. Pediatr Infect Dis J. 2006;25:761–767; doi:10.1097/01.inf.0000235678.46805.92Investigators from several Charlotte, NC institutions and the University of Minnesota, Minneapolis conducted a prospective, randomized, blinded, non-inferiority trial comparing once-daily (1xd) with twice-daily (2xd) amoxicillin for the treatment of group A ß-hemolytic streptococcal (GABHS) pharyngitis. Patients with a positive rapid GABHS test were stratified by weight and then randomly assigned to receive either 1xd amoxicillin (750 mg if <40 kg, 1000mg if ≥40 mg) or 2xd amoxicillin (375 mg 2xd if <40 kg, 500 mg 2xd if ≥40 mg) for 10 days. Of 652 patients enrolled and randomized, 590 (90%) were evaluable: 294 in the 1xd and 296 in the 2xd group. Of the 62 patients not evaluated, 45 were excluded because they did not follow up, 11 for negative cultures following a positive rapid streptococcal test, 3 because they did not take medication, and 3 who were enrolled twice and only had their first enrollment included.At visit 2 (14 to 21 days post-therapy), bacteriologic failure rates were similar between the 1xd treatment group (20.1%) and the 2xd group (15.5%, difference non-significant). The clinical recurrence rate was also comparable for the 2 treatment groups at visit 2 (9.2% 1xd vs 7.1% 2xd). At visit 3 (28 to 35 days post-therapy) the bacteriologic failure rate was significantly higher in the 2xd group (7.1% vs 2.8%). There were no significant differences in adverse events between the 2 treatment groups (gastrointestinal symptoms being most common). This study, along with previous studies,1,2 shows that 1xd amoxicillin is not inferior to 2xd amoxicillin for the treatment of GABHS pharyngitis despite the failure rate observed.Dr. Rathore has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of a commercial product/device. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.The purpose of antimicrobial therapy for GABHS pharyngitis is both for the treatment of the acute illness and for prevention of non-suppurative post-streptococcal complications.3 Dependable rapid diagnosis has made immediate treatment of GABHS pharyngitis easier, but adherence to the antibiotic regimen may be problematic. Treatment with injectable depot penicillin is the best option to assure adherence and the only one shown to decrease non-suppurative complications of GABHS pharyngitis.4 However, the intramuscular route is frequently not acceptable to patients, parents, or physicians. Oral treatment regimens for GABHS pharyngitis have improved with time. Over the years we have decreased the frequency of daily antibiotic administration from 4 times a day to twice a day for treatment of GABHS pharyngitis.5Our ability to generalize the results of this study is limited because the patients were overwhelmingly white. Despite this limitation, the findings of this preliminary study will be welcome news for many pediatricians and parents. The next steps will be to replicate the study in other population groups and then go on to test the dogma that 10 days of antibiotic therapy are necessary for treatment of GABHS. Previous investigations have shown that the pharynx is sterile within 24 hours of antibiotic treatment for GABHS pharyngitis.6 It may be that a 5- or 7-day treatment course, or perhaps an even shorter one, would be just as effective as a 10-day course. While 1xd amoxicillin should increase adherence to treatment, a shorter course of therapy, if effective, would improve adherence even more, and a single oral dose would be best of all.

Treatment of giant cell arteritis using induction therapy with high‐dose glucocorticoids: A double‐blind, placebo‐controlled, randomized prospective clinical trial

Glucocorticoid (GC) therapy for giant cell arteritis (GCA) is effective but requires prolonged administration, resulting in adverse side effects. The goal of the current study was to test the hypothesis that induction treatment with high-dose pulse intravenous (IV) methylprednisolone permits a shorter course of therapy. Twenty-seven patients with biopsy-proven GCA were enrolled in a randomized, double-blind, placebo-controlled study to receive IV methylprednisolone (15 mg/kg of ideal body weight/day) or IV saline for 3 consecutive days. All patients were started on 40 mg/day prednisone and followed the same tapering schedule as long as disease activity was controlled. The numbers of patients with disease in remission after 36, 52, and 78 weeks of treatment and taking <or=5 mg/day prednisone were compared. Cumulative prednisone dose, number of relapses, and development of adverse GC effects were assessed. Ten of the 14 IV GC-treated patients, but only 2 of 13 control patients, were taking <or=5 mg/day prednisone at 36 weeks (P = 0.003). This difference was maintained; there was a higher number of sustained remissions after discontinuation of treatment in the IV GC-treated group and a lower median daily dose of prednisone at 78 weeks (P = 0.0004). The median cumulative dose of oral prednisone, excluding the IV GC dose, was 5,636 mg in the IV GC-treated group compared with 7,860 mg in the IV saline-treated group (P = 0.001). Initial treatment of GCA with IV GC pulses allowed for more rapid tapering of oral GCs and had long-term benefits, with a higher frequency of patients experiencing sustained remission of their disease after discontinuation of treatment.

Comparison of the adverse event profiles of levofloxacin 500 mg and 750 mg in clinical trials for the treatment of respiratory infections

ABSTRACTObjective: To compare safety data with levofloxacin 500 mg and 750 mg from clinical trials for the treatment of respiratory infections.Methods: We compared adverse event data for levofloxacin 500 mg and 750 mg from clinical trials in acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and community-acquired pneumonia. Adverse events occurring after the initiation of therapy were classified as treatment-emergent adverse events (TEAE); drug-related adverse events (DRAE) were TEAE assessed by the clinical investigator as definitely/very likely or probably related to levofloxacin therapy.Results: Overall, the safety profile of the two doses was similar but not identical. TEAE occurred in 49.0% (1601/3268) of those treated with 500 mg and in 45.5% (519/1141) of those treated with 750 mg ( p = 0.042); the corresponding rates of DRAE were 7.6% (248/3268) and 8.0% (91/1141) ( p = 0.699). There was no statistically significant difference in terms of overall TEAE and DRAE rates within each of the three infectious conditions, but there were in specific events, all of which are expected with levofloxacin therapy. The limitations of this analysis include that it utilized a subset of available safety data, that it includes data only from clinical trials, and that we report primarily on events occurring in ≥ 2% of patients.Conclusions: Given similar adverse event profiles and the advantages of higher dose therapy, including shorter courses of therapy and potential impact on preventing resistance, clinicians should consider utilizing the 750 mg dose of levofloxacin when choosing between dosage strengths for treatment of indicated infections.

Short-Course PZA/RIF for Latent TB, Revisited

Shorter courses of therapy for latent TB could improve the 30% to 64% completion rates seen with 9 months of isoniazid (INH). One such regimen, 2

Clinical Trials in the Wake of Vioxx

Clinical trials have become the preeminent tool for investigating new diagnostic, therapeutic, and preventive treatment strategies. During these trials, periodic interim data analyses are conducted by data monitoring committees (DMCs) to ensure participant safety. If accumulated data indicate harm to participants, clear evidence of superior efficacy, or futility of collecting additional data, studies may be terminated before their planned conclusion. Editorial p 2173 These termination decisions are invariably complex and involve important subjective and ethical elements.1 Of greatest concern when studies are terminated because of clear benefit is the possibility that the superior intervention has toxicities that remain undiscovered. Early termination entails the abbreviation of clinical experience that would permit assessment of the longer-term safety profile. However, study continuation when treatments are not equally effective also means that some participants will continue to receive a less effective therapy. The tension between protecting both trial participants and future patients has been increasingly acute since rofecoxib (Vioxx [Merck]) and other cyclooxygenase-2 inhibitors were implicated in a greater risk of myocardial infarction. Thrombotic side effects of cyclooxygenase-2 inhibition were postulated as a result of the propensity for selective antagonists to decrease vascular prostacyclin production and possibly affect the balance between prothrombotic and antithrombotic eicosanoids.2 Little evidence of toxicity was evident in preapproval trials, however, and rofecoxib was approved in 1999 for relief of the signs and symptoms of osteoarthritis, the management of acute pain, and the treatment of primary dysmennorhea.3 The possibility of cardiac toxicity in human trials was recognized in the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial.4 Meta-analyses, database studies, and prospective trials further corroborated cardiac toxicity,5–8 and Merck voluntarily withdrew rofecoxib from the US market on September 30, 2004,9 amid widespread criticism of both Merck and the Food and Drug Administration.10,11 In the wake …

Exendin-4 treatment improves metabolic control after rat islet transplantation to athymic mice with streptozotocin-induced diabetes

Early islet graft survival is crucial in determining the outcome after clinical islet transplantation. Exendin-4 has anti-apoptotic and beta cell proliferative properties, which could improve islet graft survival and function. The aim of these studies was to evaluate the effect of exendin-4 on graft function after islet transplantation. Rat islets were transplanted under the kidney capsule of diabetic athymic mice. First, we performed a dose-finding study and found that 30 islets just failed to cure diabetic mice. In the following two studies, we transplanted 30 islets and treated the mice that had received these islets with exendin-4 i.p. (100 ng/mouse) once daily for 1 week. Blood glucose levels and body weights were used as evaluation criteria. In the short-term study evaluation was done at day 8. This study was followed by a long-term study that was evaluated at 4 weeks. In this study, islets were precultured with exendin-4 (0.1 nmol/l) in addition to the treatment given to mouse-recipients of transplanted islets. The cured mice underwent an intraperitoneal glucose tolerance test (IPGTT). In the short-term study, 63% of exendin-4-treated mice achieved graft function compared with 21% of untreated mice (p = 0.033). In the long-term study, 88% of treated mice had functioning grafts compared with 22% of controls (p = 0.015). Cured mice showed a normal response in the IPGTT, comparable to that of healthy mice. Exendin-4-treated mice gained significantly more weight than their untreated counterparts. Islet preculture and a short course of therapy with exendin-4 improves metabolic control after rat islet transplantation in athymic mice. The beneficial effect lasts beyond the treatment period.

Time to Screen for Congenital Toxoplasmosis?

Although the devastating consequences of congenital toxoplasmosis are well known as part of the TORCH syndrome (i.e., toxoplasmosis, syphilis, rubella, cytomegalovirus, and herpes infections), many aspects of surveillance and treatment of congenital toxoplasmosis have remained controversial because of incomplete data regarding the prevalence of disease and the impact of treatment. McLeod et al. [1] now report the results of a longitudinal study that shows the significant impact of treatment on 120 congenitally infected children who were treated for 1 year with pyrimethamine and sulfadiazine. The National Collaborative Chicago-Based, Congenital Toxoplasmosis Study has been observing affected children prospectively since 1981 [2]. Currently, the 1-year treatment regimen is the standard of care in the United States for congenital toxoplasmosis, but the long-term impact of treatment was unknown. Interim reports about this cohort of children have been previously published [2]. A prospective, doubleblind study including an arm of untreated patients was deemed ethically contraindicated because of unexpectedly favorable results of pilot treatment studies. As a result, outcomes were compiled for children treated with 2 regimens of pyrimethamine and sulfadiazine for 1 year and compared with outcomes of children in previously published studies. Prior studies had shown that untreated children or children who received a short course of therapy (1 month) did poorly [3, 4]. Children in the study by McLeod et al. [1] were examined for specific end points that included motor abnormalities,

Are Shorter Courses of Filgrastim Prophylaxis Associated with Increased Risk of Hospitalization?

In clinical trials in patients receiving myelosuppressive chemotherapy, 10-11 days of prophylaxis with filgrastim has been found to reduce the incidence of febrile neutropenia. In clinical practice, however, many patients receive shorter courses of therapy, even though the effectiveness of this regimen is unknown. To examine the relationship between duration of filgrastim prophylaxis and risk of hospitalization in patients receiving chemotherapy for non-Hodgkin's lymphoma (NHL), breast cancer, or lung cancer. Using a large, automated, US healthcare claims database, we identified all adults who received chemotherapy for NHL, breast cancer, or lung cancer between 1998 and 2002. For these patients, we identified their first course of chemotherapy and each unique cycle within that course. We then focused attention on all patient cycles in which filgrastim was administered on or before cycle day 5 (filgrastim prophylaxis). Pooling all such cycles, we examined the relationship between duration of filgrastim prophylaxis and risk of hospitalization for neutropenia or infection and risk of hospitalization for any reason, using generalized estimating equations. Mean +/- SD duration of filgrastim prophylaxis was 6.5 +/- 3.1 days across 332 cycles for 133 NHL patients, 6.1 +/- 2.9 days across 482 cycles for 205 breast cancer patients, and 4.3 +/- 3.1 days across 522 cycles for 260 lung cancer patients. In multivariate analyses, risk of hospitalization for neutropenia or infection was found to decline with each additional day of filgrastim prophylaxis for patients with NHL (OR 0.81; p = 0.003), breast cancer (OR 0.77; p = 0.001), and lung cancer (OR 0.91; p = 0.084). Risk reductions with each additional day of prophylaxis ranged from 15% to 19% for patients with NHL, 17% to 23% for those with breast cancer, and 8% to 9% for those with lung cancer. Similar reductions in risk were noted for all-cause hospitalization. Among patients with NHL, breast cancer, or lung cancer, shorter courses of filgrastim prophylaxis may increase the risk of hospitalization.

Peginterferon Alfa-2b and Ribavirin for 12 vs. 24 Weeks in HCV Genotype 2 or 3

We hypothesized that in patients with hepatitis C virus (HCV) genotype 2 or 3 in whom HCV RNA is not detectable after 4 weeks of therapy, 12 weeks of treatment is as effective as 24 weeks. A total of 283 patients were randomly assigned to a standard 24-week regimen of peginterferon alfa-2b at a dose of 1.0 mug per kilogram weekly plus ribavirin at a dose of 1000 mg or 1200 mg daily, on the basis of body weight. Of these, 70 patients were assigned to the 24-week regimen (standard-duration group) and 213 patients to a variable regimen (variable-duration group) of 12 or 24 weeks, depending on whether tests for HCV RNA were negative or positive at week 4. The primary end point was HCV that was not detectable by polymerase-chain-reaction (PCR) assay 24 weeks after the completion of therapy. In the standard-duration group, 45 (64 percent) patients had HCV that was not detectable by PCR assay at week 4, as compared with 133 (62 percent) in the variable-duration group (difference [the rate in the standard-duration group minus that in the variable-duration group], 2 percent; 95 percent confidence interval, -11 to 15 percent). Fifty-three patients (76 percent) in the standard-duration group and 164 patients (77 percent) in the variable-duration group had a sustained virologic response (difference, -1 percent; 95 percent confidence interval, -13 to 10 percent). Fewer patients in the variable-duration group receiving the 12-week regimen had adverse events and withdrew than in the group receiving the 24-week regimen (P=0.045). The rate of relapse (defined as HCV not detectable at the end of treatment but detectable at the end of follow-up) was 3.6 percent in the standard-duration group and 8.9 percent in the variable-duration group (P=0.16). Overall, the rate of sustained virologic response was 80 percent among patients with HCV genotype 2 and 66 percent among those with genotype 3 (P<0.001). A shorter course of therapy over 12 weeks with peginterferon alfa-2b and ribavirin is as effective as a 24-week course for patients with HCV genotype 2 or 3 who have a response to treatment at 4 weeks.