Concomitant use of direct-acting antivirals and chemotherapy in hepatitis C virus-infected patients with cancer.

BACKGROUND: Antiviral therapy improves hepatic outcomes in hepatitis C virus (HCV)-infected cancer patients. However, such patients are not treated simultaneously with antivirals and chemotherapy, owing to overlapping toxicities with previous standard of care treatment of pegylated interferon and ribavirin. AIM: To examine the safety and clinically-significant drug-drug interactions observed in patients who received simultaneous treatment with direct-acting antivirals (DAAs) and chemotherapy. METHODS: Safety was determined by the presence of adverse events which were graded according to the division of AIDS Table (version 2.0). Adverse events were monitored throughout antiviral treatment and up to 3 months after its completion. Drug-drug interactions were assessed using current online databases. Sustained virological response (SVR) was defined as absence of serum HCV RNA 12 weeks after end of DAA treatment. Cirrhosis was diagnosed via imaging, biopsy or with the use of non-invasive fibrosis markers. RESULTS: Twenty-one patients received concomitant treatment with DAAs and chemotherapy between January 2013 and September 2016. Concomitant treatment was started either for virological (14; 67%) or oncologic (7; 33%) reasons. DAAs used were sofosbuvir, ledipasvir, simeprevir, daclatasvir ± ribavirin. The adverse events observed were mainly constitutional (12; 57%), hematological and gastrointestinal (7; 33% each). Physicians changed the DAA regimens in two patients (10%) in anticipation of drug-drug interactions with daclatasvir and dexamethasone. The overall SVR rate was 95% (20/21). CONCLUSIONS: Hepatitis C virus-targeted antiviral therapy can be used concomitantly with selected anti-neoplastic agents under close monitoring for drug-drug interactions. This therapeutic intervention may prevent delay in the administration of chemotherapy in HCV-infected cancer patients.

Initial use of combination treatment does not impact survival of 106 patients with haematologic malignancies and mucormycosis: a propensity score analysis.

In view of the poor outcomes associated with mucormycosis in patients with haematologic malignancies (HM) and haematopoietic cell transplant recipients, antifungal combinations are frequently used, yet the value of such strategy remains unclear. We reviewed the records of HM patients treated for mucormycosis from 1994 to 2014. The primary outcome was 6-week mortality after treatment initiation. Of the 106 patients identified, 44% received monotherapy and 56% received combination treatment as initial therapy. Six-week mortality was associated with disseminated mucormycosis (p 0.018), active malignancy (p <0.01), higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores (p <0.001), neutropenia (p 0.049), lymphopenia (p 0.0003) and intensive care unit (ICU) admission at diagnosis (p 0.0001). Survivors were more likely to have localized mucormycosis (p <0.01) and to receive hyperbaric oxygen therapy (p 0.02). There were no differences in mortality between monotherapy and combination treatment groups (43% vs. 41%; p 0.85). In multivariate analysis, lymphopenia (odds ratio (OR), 5.5; 95% confidence interval (CI), 1.9-15.9; p 0.002) and ICU admission at diagnosis (OR, 8.2; 95% CI, 2.3-29.2; p 0.001) were associated with increased mortality. Localized mucormycosis was associated with better outcome (OR, 0.06; 95% CI, 0.01-0.6; p 0.019). Initial combination treatment had no impact on mortality, even after propensity score adjustment (OR, 0.8; 95% CI, 0.3-2.4; p 0.69). A weighted mortality risk score was then calculated for each patient based on the factors independently associated with mortality and baseline APACHE II score. In the low-risk group (n = 49), 13% of monotherapy versus 15% of combination therapy patients died within 6 weeks (p >0.99). In the high-risk group (n = 57), 71% of monotherapy versus 61% of combination therapy patients died within 6 weeks (p 0.42). With the current status of mucormycosis diagnosis, there was no difference in mortality in HM patients, whether they received monotherapy or combination treatment as initial therapy. Earlier diagnosis and immune reconstitution are unmet needs to affect outcomes.

Early initiation of appropriate treatment is associated with increased survival in cancer patients with Candida glabrata fungaemia: a potential benefit from infectious disease consultation.

In patients with malignancies, Candida glabrata is one of the most frequent non-albicans Candida clinical isolates. As antifungal resistance in C. glabrata is common, we investigated the relationship between early appropriate antifungal treatment, infectious disease (ID) consultation and mortality in a contemporary cohort of cancer patients with C. glabrata fungaemia. We included patients with at least one C. glabrata-positive blood culture and symptoms or signs of infection seen at the MD Anderson Cancer Center between March 2005 and September 2013. In vitro susceptibility to antifungals was defined according to the 2010 CLSI clinical breakpoints. One-hundred and forty-six episodes of candidaemia were studied. Thirty isolates (20.5%) had fluconazole MIC ≥ 64 mg/L and 15 (10.3%) were caspofungin-resistant. Early (within 48 h after blood culture collection) initiation of appropriate antifungal treatment (hazard ratio 0.374, p 0.003) and early ID consultation (hazard ratio 0.421, p 0.004) were associated with decreased mortality, after adjustment for significant confounders. Thirty-two of 58 patients (55.2%) followed by ID were on appropriate antifungals within 48 h, compared with 16/88 patients (18.2%) who were not followed by ID an ID specialist (p <0.001). The median time-to-reporting of blood culture positivity for yeast was 71 h. Delayed time-to-reporting was associated with increased 28-day all-cause mortality (log-rank p 0.023). The benefits from early initiation of appropriate antifungal treatment and ID consultation were more prominent in patients with non-catheter-related candidaemia. In conclusion, in cancer patients with C. glabrata fungaemia, early ID consultation may lead to timely initiation of appropriate treatment and improved clinical outcomes.

Trends of vaginal birth after cesarean delivery in Germany from 1990 to 2012: a population-based study.

BACKGROUND: The increasing incidence of cesarean deliveries (CD) in the western world is consequently leading to a rising number of antenatal counselling of pregnant women with a history of previous CD. To counteract the increasing trend of cesarean deliveries, the concept of vaginal birth after cesarean delivery (VBAC) may represent an alternative. The aim of the present study was to longitudinally investigate the incidence of VBAC and compare the changes within all deliveries during 23 years of follow-up. METHODS: In this study we analyzed data from 1 202 557 deliveries in Hesse, Germany from 1990 to 2012. In total, 131 629 births have been identified to have at least one CD in the patients' medical history. We grouped the patients into 3 categories: vaginal spontaneous birth subsequent to CD, vaginal-operative birth subsequent to CD and repeated CD. RESULTS: After previous CD, 32.1% of the patients delivered spontaneously, 4.0% delivered vaginal-operative and 63.8% had a repeated CD. The rates changed from 40.4, 7.5 and 52.1% in the year 1990 to 23.3, 2.8 and 73.9% in the year 2012 for vaginal spontaneous births, vaginal-operative births and for repeated CDs, respectively (p<0.01). We noticed a decline of 17.1 and 4.7% in spontaneous births after Cesarean and vaginal operative births respectively during the observation period. Notably, we report a dramatic increase of 21.8% of repeated CDs during the past 23 years (p<0.01). With regard to the non-affected group including all deliveries, we observed a decrease of 17% in spontaneous deliveries from 1990 to 2012 (75.9 vs. 58.9%). Vaginal operative delivery rates changed from 6.9% in 1990 to 5.9% in 2012. Consequently, CD rates increased from 17.2% in 1990 to 35.2% in the year 2012 (p<0.01). The differences between all 3 subgroups were significantly different (p<0.001). DISCUSSION: Cesarean rates in Germany have reached an all-time high, while VBAC follows a continuous decrease. The current rate of VBAC is almost the half of that in the year 1990 (26.1 vs. 47.9%). Promotion of a trial of labor (TOL) after low transverse CD in those women who desire 3 or more children may increase the VBAC success rates and reduce maternal morbidity.

Efficacy and safety of antiretrovirals in HIV-infected patients with cancer.

At 30 years into the HIV infection epidemic, the optimal antiretroviral (ARV) regimen for infected patients with cancer remains unknown. We therefore sought to retrospectively study different ARV regimens used in this population. Data from HIV-infected patients seen at The University of Texas MD Anderson Cancer Center in Houston, Texas, USA, from 2001 to 2012 were reviewed. Patients received nucleoside reverse transcriptase inhibitors (NRTIs) plus protease inhibitors (PIs), non-NRTIs (NNRTIs), integrase strand-transfer inhibitors (INSTIs), or combinations of these. A total of 154 patients were studied. Most patients were male (80%), white (51%) and had haematological malignancies (HMs) (58%). NRTIs were combined with PIs (37%), NNRTIs (32%), INSTIs (19%) or combinations of these (11%). INSTIs were the most commonly used in patients with HM and in those receiving high-dose steroids or topoisomerase inhibitors (p <0.05). Side-effects occurred in 35%, 14%, 3% and 6% of patients receiving PIs, NNRTIs, INSTIs and combinations, respectively (p 0.001). Grade 3-4 adverse events were uncommon. Multivariate logistic regression analysis demonstrated that INSTIs and NNRTIs were nine times (95% confidence interval (CI), 1.4-50.8) and 11 times (95% CI, 1.9-64.7) more likely to be effective at 6 months, respectively, than PIs. This is the largest reported analysis studying different ARV regimens in HIV-infected cancer patients. Combinations that included PIs were the least favourable. NNRTIs and INSTIs had comparable efficacy, but INSTIs appeared to be the better tolerated ARVs in patients with HM or those receiving various chemotherapeutic agents.

Rising cesarean rates of twin deliveries in Germany from 1990 to 2012.

In the past 2 decades there has been an increasing trend for cesarean deliveries in twin pregnancies associated with increased maternal and fetal morbidity and mortality.We analyzed the mode of delivery of 18,132 twin gestations from the perinatal survey of Hessen in Germany between 1990 and 2012 and divided them into 4 categories according to the week of gestation (<28, 28-31, 32-36, >36). We further analyzed the cesarean delivery rates for the same period depending on the institutional level and divided them into 3 categories - University hospitals with perinatal center (U/PS), non-university affiliated hospitals with perinatal center (NU/PS) and smaller clinics without perinatal unit (NU/NPS).Cesarean rates changed from 63.6% (< 28), 88.9% (28-31), 59.6% (32-36) and 40% (> 36) in the year 1990 to 74.2%, 95.5%, 76.9% and 68.7% in 2012, respectively. As such, we report an overall increase of 23.5% in cesarean deliveries of twins over the last 23 years. We find an overall increase of 16.8%, 21% and 22.1% in university hospitals with perinatal units, in non-university hospitals with perinatal unit and in smaller hospitals without perinatal units, respectively. Furthermore, combined cesareans increased from 3.9% in 1990 to 7.0% in 2012.These findings indicate a dramatic increase in cesarean delivery rates for twin births from 1990 to 2012. We discuss the importance of international compatible guidelines for the conditions and technical procedures for twin deliveries.