Two-drug Group Research Articles

Macrolide resistant Mycobacterium avium complex pulmonary disease following clarithromycin and ethambutol combination therapy.

Whether two-drug therapy (clarithromycin and ethambutol) for Mycobacterium avium complex (MAC) pulmonary disease contributes to the development of macrolide-resistant MAC is unclear. To compare the incidence of macrolide-resistant MAC between patients treated with two-drug therapy (clarithromycin and ethambutol) and the standard three-drug therapy (clarithromycin, ethambutol, and rifampicin) for MAC pulmonary disease. We retrospectively reviewed 147 patients with treatment-naive MAC pulmonary disease who had received two-drug therapy (n=47) or three-drug therapy (n=100) between 1997 and 2016at National Hospital Organization, Tenryu Hospital, Hamamatsu, Japan. The risk of development of macrolide-resistant MAC was evaluated by calculating the cumulative incidence rate using Gray's test. The median follow-up period was 74.5 months. During the follow-up period, one of the 47 patients (2.1%) in the two-drug group developed macrolide-resistant MAC, compared to 12 of the 100 patients (12.0%) in the three-drug group. The cumulative incidence rate of macrolide-resistant MAC was lower in the two-drug group than in the three-drug group (0.0023; 95% confidence interval, 0.002 to 0.107 versus 0.200; 95% confidence interval, 0.100 to 0.324, p=0.0593). These results suggest that two-drug treatment with clarithromycin and ethambutol for MAC pulmonary disease does not lead to a higher incidence of resistance acquisition to clarithromycin than the standard three-drug treatment.

Impact of Combination Chemotherapy in Peritoneal Mesothelioma Hyperthermic Intraperitoneal Chemotherapy (HIPEC): The RENAPE Study.

The introduction of cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) improved the prognosis of selected patients with peritoneal mesothelioma (PM). The objective of our study was to evaluate whether different HIPEC agents were associated with different outcomes in patients with PM. From the RENAPE database, we selected all patients with histology-proven PM who underwent CRS + HIPEC from 1989 to 2014. Inclusion criteria were age ≤ 80years, performance status ≤ 2, and no extraperitoneal metastases. Overall, 249 patients underwent CRS + HIPEC for PM. The HIPEC regimen included five chemotherapeutic agents (CAs), consisting of cisplatin, doxorubicin, mitomycin-C, oxaliplatin, and irinotecan. When considering all CAs (alone or in combination), there was no significant statistical difference in regard to postoperative overall survival (OS). However, OS was better when using two CAs (group 2 drugs) versus one CA (group1 drug) (p = 0.03). The different CA regimens were equally distributed between the two groups. This association between OS and HIPEC agent, as well as a trend for better progression-free survival, were both observed in the two-drug group versus the one-drug group (p = 0.009) for patients undergoing complete cytoreductive surgery (CC-0) with an epithelioid subtype. This large study seems to show improved OS when combined CAs, especially with platinum-based regimens, are used for HIPEC in patients with PM, but needs to be confirmed by a randomized controlled trial.

Comparison of therapeutic efficacy of different chemotherapeutic regimens on combined small cell lung cancer

response rates between the three-drug and two-drug groups were statistically significant (90% vs. 53%, P=0.033). However, no statistical differences were observed in the disease control rate between the two groups (100% vs. 86%, P=0.212). The three-drug regimen could induce a better median progression-free survival compared with the two-drug regimen, but with no statistical significance (10.5% vs. 9.8%, P=0.484). Similarly, no statistical differences were noted in the median overall survival between the three-drug and two-drug groups (24.0% vs. 17.5%, P=0.457). The incidence rates of grade IV bone marrow depression and the termination of the original regimen owing to severe adverse reactions were both significantly higher in the three-drug group than in the two-drug group (26.3% vs. 7.0%, P=0.036; 31.6% vs. 14.7%, P=0.004). Conclusion: The two-drug regimen had almost the same survival rate and lower toxicity compared with the three-drug regimen. When using the TEP/TCE regimen, a close attention should be focused on its adverse reactions. The findings of this work showed that the two-agent regimen should be one of the standard treatments for CSCLC.

Impact of number of lines of therapy following docetaxel (D) in metastatic castration-resistant prostate cancer (mCRPC).

223 Background: The impact of number of lines of therapy on outcomes following docetaxel (D) in metastatic castration-resistant prostate cancer (mCRPC) is unclear. We examined outcomes with cabazitaxel (C) and/or abiraterone acetate (A), following D during a period when all three therapies were available. We previously reported that most patients received only two of these three therapies. Among patients who received all three, DCA was administered more commonly and exhibited better overall survival (OS) than DAC after controlling for prognostic factors. Here, we report the impact of number of lines of therapy following D. Methods: A retrospective analysis of the U.S. Oncology network electronic health records (EHR) was conducted of post-D patients with mCRPC who received C and/or A from April 2011 to May 2012. Median OS was analyzed by Kaplan-Meier method. Cox proportional hazard models were used to evaluate impact on OS of number of therapies administered, age, Prostate Cancer Working Group (PCWG2) subtype, Charlson comorbidity index, prostate-specific antigen (PSA), alkaline phosphatase, hemoglobin, narcotic use, and treatment duration. Results: Multivariate analysis showed significantly lower mortality in the three-drug group compared to the two-drug group (HR 0.209 95% CI: 0.092-0.476, p<0.05). 113 patients received three drugs (DCA=77, DAC=36) and 237 received two drugs (DA=183, DC=54). The three-drug cohort was significantly younger than the two-drug group (median age 69 vs. 73). Other significant covariates (p<0.05) for mortality were narcotic use (HR 2.010 [1.240-3.259]), PSA (HR 1.014 [1.001-1.027] and alkaline phosphatase (HR 1.001 [1.000-1.001]. Conclusions: In men with mCRPC receiving C and/or A post-D, patients receiving all three therapies were younger and exhibited significantly better OS after controlling for clinical factors. In those receiving only two therapies, there appeared to be no difference in outcomes for second-line C versus A. Given the favorable impact of receiving all three therapies, more frequent administration of DCA in the three-drug group and better OS for DCA compared to DAC, we hypothesize that DCA may be a more optimal sequence. These results are exploratory and prospective validation is necessary.

Three Postpartum Antiretroviral Regimens to Prevent Intrapartum HIV Infection

BackgroundThe safety and efficacy of adding antiretroviral drugs to standard zidovudine prophylaxis in infants of mothers with human immunodeficiency virus (HIV) infection who did not receive antenatal antiretroviral therapy (ART) because of late identification are unclear. We evaluated three ART regimens in such infants.MethodsWithin 48 hours after their birth, we randomly assigned formula-fed infants born to women with a peripartum diagnosis of HIV type 1 (HIV-1) infection to one of three regimens: zidovudine for 6 weeks (zidovudine-alone group), zidovudine for 6 weeks plus three doses of nevirapine during the first 8 days of life (two-drug group), or zidovudine for 6 weeks plus nelfinavir and lamivudine for 2 weeks (three-drug group). The primary outcome was HIV-1 infection at 3 months in infants uninfected at birth.ResultsA total of 1684 infants were enrolled in the Americas and South Africa (566 in the zidovudine-alone group, 562 in the two-drug group, and 556 in the three-drug group). The overall rate of in utero transmission of HIV-1 on the basis of Kaplan–Meier estimates was 5.7% (93 infants), with no significant differences among the groups. Intrapartum transmission occurred in 24 infants in the zidovudine-alone group (4.8%; 95% confidence interval [CI], 3.2 to 7.1), as compared with 11 infants in the two-drug group (2.2%; 95% CI, 1.2 to 3.9; P=0.046) and 12 in the three-drug group (2.4%; 95% CI, 1.4 to 4.3; P=0.046). The overall transmission rate was 8.5% (140 infants), with an increased rate in the zidovudine-alone group (P=0.03 for the comparisons with the two- and three-drug groups). On multivariate analysis, zidovudine monotherapy, a higher maternal viral load, and maternal use of illegal substances were significantly associated with transmission. The rate of neutropenia was significantly increased in the three-drug group (P<0.001 for both comparisons with the other groups).ConclusionsIn neonates whose mothers did not receive ART during pregnancy, prophylaxis with a two- or three-drug ART regimen is superior to zidovudine alone for the prevention of intrapartum HIV transmission; the two-drug regimen has less toxicity than the three-drug regimen. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD] and others; ClinicalTrials.gov number, NCT00099359.)

A novel neurotrophic therapeutic strategy for experimental stroke

Human chorionic gonadotropin (hCG) promotes proliferation of endogenous neural stem cells, and erythropoietin (EPO) promotes differentiation of these cells into neural stem cells. The current study examined effects of sequential administration of these two compounds, initiated 24 h after stroke. At that time, rats were randomized into four treatment groups: hCG+EPO (3 IM doses hCG over 5 days, followed by 3 IV doses EPO over 3 days), hCG+Saline using the same schedule, Saline+EPO using the same schedule, or neither drug (Saline+Saline). The primary endpoint was the composite neurological score, measured 11 times, from 1 h until 12 weeks post-insult. The neurological score was different across treatment groups ( p < 0.03). Pairwise testing of groups found that the hCG+EPO group had significantly better behavior at 6/10 post-stroke time points as compared to Saline+Saline. The differences observed when comparing the two-drug group with placebo were less apparent when comparing either of the one-drug groups with placebo. The two one-drug treatment arms did not significantly differ at any time point. Treatment with hCG+EPO significantly reduced total lesion volume by 82–89% compared to the other three treatment groups. The current therapeutic strategy improved behavioral outcome and reduced lesion volume with a time window of 24 h after the onset of stroke. The results from these experiments provide new insight into the effects of these two growth factors on stroke in rats, and could suggest a potential for translation into human stroke studies.

A randomized trial of two-drug versus three-drug tenofovir-containing maintenance regimens in virologically controlled HIV-1 patients

To assess simplified maintenance regimens containing dual antiretroviral drugs in patients with controlled human immunodeficiency virus type 1 infection. A non-inferiority, randomized, multicentre, open-label trial was performed in 24 AIDS clinical centres in France randomizing 143 patients [treated for >or=6 months, plasma viral load (pVL) <50 copies/mL, no prior history of treatment failure] to receive a two-drug regimen [tenofovir disoproxil fumarate (tenofovir DF) and efavirenz] or to maintain a three-drug treatment (tenofovir DF, lamivudine and efavirenz). The main outcome measure was the success rate (percentage of patients with pVL <50 copies/mL without treatment modifications) at week 48. Success rates for the intention-to-treat analysis were 97.2% (70/72) versus 81.7% (58/71) in the three-drug versus two-drug maintenance regimen groups, respectively [difference, 15.5%; upper limit of one-sided 95% confidence interval (CI), 23.7%], and 100% (70/70) versus 90% (54/60) for the per protocol analysis, respectively (difference, 10%; upper limit of one-sided 95% CI, 16.4%), with a non-inferiority margin set at 14%. Three patients from the two-drug group experienced virological failure with selection of efavirenz-associated mutations. Overall, CD4 counts were significantly increased from baseline (median, +24 cells/mm(3); P = 0.007). Four patients discontinued study treatment due to adverse events in the two-drug group and none in the three-drug group. No significant changes in creatinine clearance or phosphataemia were reported. Overall, levels of triglycerides, total and high-density lipoprotein cholesterol were improved; low-density lipoprotein cholesterol was improved only in the three-drug group. The non-inferiority of the two-drug versus the three-drug regimen was not demonstrated. Lipid parameters improved after switching from twice-daily highly active antiretroviral therapy (HAART) to once-daily tenofovir-based HAART.

Adherence in Glaucoma: Objective Measurements of Once-Daily and Adjunctive Medication Use

To determine with electronic monitoring an objective measurement of adherence in two populations of subjects: those using once-daily prostaglandin analogs as sole ocular hypotensive therapy (one-drug group) and those requiring an adjunctive medicine to the prostaglandin analog (two-drug group). Single-site, open-label, nonrandomized, parallel design of 60 days. Sixty-two consecutive adult subjects with a diagnosis of open-angle glaucoma (OAG) or ocular hypertension: 31 were taking one drug and 31 were taking two drugs. An electronic event medication monitoring device was used to record each bottle opening. The main outcome measures were dosing errors (number of under-adherence or over-adherence events) and coverage (proportion of pharmacologic duration covered by dosing) relative to the ophthalmologist-prescribed regimen. Adherence to the prostaglandins once daily was good in both groups by all measures (<or=10% of subjects with more than five dosing errors and mean coverage of 97.2% +/- 6.1%). Adherence to the second medication in the two-drug group was poorer (37% of subjects with more than five dosing errors and mean coverage of 85.6% +/- 12.6%). For the subjects using beta-adrenoceptor antagonists, 24.8% +/- 18.4% of doses were taken at less than 10-hour intervals (over-adherence). The incorporation of a time component in electronic monitoring provides more information than prescription refill rate or other methods. We found that more complex dosing regimens result in poorer adherence, although once-daily drugs in a complex dosing regimen were found to have good adherence.

Increased septic complications with three-drug sequential immunosuppression for cadaver renal transplants

In 152 renal transplant recipients, the results of immunosuppression with three-drug sequential (Minnesota antilymphocyte globulin, prednisone, azathioprine, and cyclosporine) immunosuppression (n = 107) were compared with those of a two-drug sequential protocol (Minnesota antilymphocyte globulin, prednisone, and cyclosporine) that excluded azathioprine (n = 45). The study groups were comparable by age, sex, etiology of renal failure, incidence of diabetes, and degree of HLA matching. Patient survival at 1 year was not significantly different in the two groups (two drug, 93% versus three drug, 86%; p = 0.19). One-year graft survival was superior in the two-drug group (two drug, 93% versus three drug, 75%; p = 0.02). Analysis of primary transplants only (n = 116) yielded the same results. During the first year, the serum creatinine level remained stable in both groups. As expected, the three-drug therapy group had significantly more bacterial and viral infections. For low-risk primary cadaveric renal transplants, two-drug sequential immunosuppression is superior.

Long-term maintenance of therapeutic response to lovastatin in patients with familial and non-familial hypercholesterolemia: a 3-year follow-up

The 3-year efficacy of lovastatin alone or in combination with colestipol was evaluated in 54 patients with type 2 hyperlipoproteinemia (22 non-familial and 32 familial hypercholesterolemic patients). A sufficient and sustained reduction in LDL cholesterol was achieved in non-familial hypercholesterolemia with lovastatin alone (average dose 74 mg/day, range 40–80 mg/d), whereas combination therapy with lovastatin 80 mg/d and colestipol (average dose 11.9 g/d, range 5–20 g/d) was required in familial hypercholesterolemia. The percentage changes from baseline at 3 years in serum LDL cholesterol, HDL cholesterol and total triglycerides were in the lovastatin-only group - 53%, + 10% and -15%, respectively, and in the two-drug group -58%, +22% and -18%, respectively. A subgroup analysis in patients with non-familial hypercholesterolemia indicated that the lipid-modifying effects of lovastatin were similar in type 2A and 2B phenotypes, except for a greater triglyceride lowering effect in type 2B. The lovastatin-alone regimen was well tolerated, whereas addition of colestipol caused subjective side effects in many patients. Serious side effects or discontinuations due to therapies did not occur. Both therapies caused slight but significant increases (within normal limits) in average serum transaminase levels. After 36 months a significant rise of 1.7 kg in mean body weight was observed in the lovastatin-only group. The ophthalmological follow-up did not reveal any cataractogenic effect attributable to treatment during the 3.8-year follow-up period.

Pancreatic Cancer Treated With Carmustine, Fluorouracil, and Spironolactone

A prospective randomized trial between two drug regimens in 38 patients with advanced pancreatic carcinoma was performed. The two-drug regimen consisted of carmustine and fluorouracil. The survival rate and response to these two drugs was compared to a three-drug regimen consisting of these same two drugs plus spironolactone. Objective partial responses were rare in both groups, being 3/18 in the two-drug group and 2/20 in the three-drug group. Life table analysis in previously untreated patients from time of treatment shows longer survival for the three-drug group, but this difference was not statistically significant.

The results of treatment in patients with cultures resistant to streptomycin, isoniazid and PAS: A five-year follow-up

Summary The late results, five years after the start of treatment, are given in 122 patients with far-advanced tuberculosis and cultures resistant to streptomycin, isoniazid and PAS. Thirty-nine had chemotherapy and early surgical treatment and 83 had chemotherapy alone (surgical treatment was used in four after a relapse). The following drugs were used: ethionamide (0·5 g, twice daily), pyrazinamide (0·5 g. three times daily), cycloserine (0·25 g. three times daily), viomycin (1 g. daily or 2 g, twice a week). Fifty-five of the 83 patients were treated initially with three of the secondary drugs for a minimum of three months and an average period of 12 months; treatment was then continued with two drugs. Fifty-three (96%) became negative on culture. In two patients the treatment failed initially; both had one of the drugs (viomycin) intermittently and, as discovered later, one had no appreciable concentration of ethionamide in the serum after either oral or rectal administration of the drug. Eight (14%) had a late bacteriological relapse. They did not take drugs regularly. In four of them the cultures became resistant to secondary drugs. Five became negative again with further treatment (two of them after surgery). Ten patients died, six of them after the sputum had become persistently negative. Twenty-eight patients had only one or two drugs initially: only 11 (40%) became negative, three of them after retreatment with three-drug combinations. Nineteen died and in 16 of these sputum was still positive. There was no significant difference between the three-drug and two-drug group in the severity of disease and other relevant factors. The difficulties of treatment with secondary drugs are emphasized. However, satisfactory long-term results can be obtained if some basic rules and principles of good chemotherapy are observed, and if the patients are willing to co-operate.