Diarrhea, CD4 counts and enteric infections in a hospital - based cohort of HIV-infected patients around Varanasi, India

Background: As most of the studies in HIV patients with diarrhea were cross sectional, focusing on the etiological agents, we are reporting data on the rate of diarrhea, associations between diarrhea and CD4 counts and variation in frequency of identifying a pathogen with consistency of diarrhea and duration in a prospective hospital based study. Methods: Stool specimens were obtained between Jan 2001 and April 2003 from HIV infected adults with diarrhea presenting to Infectious Disease clinic, Banaras Hindu University, Varanasi. In all patients with diarrhea, specimens were examined by microscopy and cultures to identify pathogens. Results: During the study, 630 person years of observations with diarrhea were analyzed. 140 stool samples were collected representing 43% of episodes of reported diarrhea. Positivity of finding a pathogen from watery stools and formed stools were 40%&24% respectively (p < 0.01) probably due to associated inflammation is more in watery diarrhea. Patients having chronic diarrhea are 2.25 (95%CI 1.52-2.81) times at more risk of developing other opportunistic infections compared to those who don't have. However this is not true with the acute diarrhea where risk of harboring the opportunistic infections remain same. Conclusion: Diarrhea was most strongly associated with low CD4 counts. Over two-thirds of diarrheal episodes were undiagnosed, suggesting that unidentified agents or primary HIV enteropathy are important causes of diarrhea in this population. There is a strong negative association between duration of diarrhea and CD4 levels

Correlation between CD4 counts of HIV patients and enteric protozoan in different seasons – An experience of a tertiary care hospital in Varanasi (India)

<p>Abstract</p> <p>Background</p> <p>Protozoan infections are the most serious among all the superimposed infections in HIV patients and claim a number of lives every year. The line of treatment being different for diverse parasites necessitates a definitive diagnosis of the etiological agents to avoid empirical treatment. Thus, the present study has been aimed to elucidate the associations between diarrhoea and CD4 counts and to study the effect of HAART along with management of diarrhoea in HIV positive patients. This study is the first of its kind in this area where an attempt was made to correlate seasonal variation and intestinal protozoan infestations.</p> <p>Methods</p> <p>The study period was from January 2006 to October 2007 wherein stool samples were collected from 366 HIV positive patients with diarrhea attending the ART centre, inpatient department and ICTC of S.S. hospital, I.M.S., B.H.U., Varanasi. Simultaneously, CD4 counts were recorded to assess the status of HIV infection vis-à-vis parasitic infection. The identification of pathogens was done on the basis of direct microscopy and different staining techniques.</p> <p>Results</p> <p>Of the 366 patients, 112 had acute and 254 had chronic diarrhea. The percentages of intestinal protozoa detected were 78.5% in acute and 50.7% in chronic cases respectively. Immune restoration was observed in 36.6% patients after treatment on the basis of clinical observation and CD4 counts. In 39.8% of HIV positive cases <it>Cryptosporidium </it>spp. was detected followed by <it>Microsporidia </it>spp. (26.7%). The highest incidence of intestinal infection was in the rainy season. However, infection with <it>Cyclospora </it>spp. was at its peak in the summer. Patients with chronic diarrhea had lower CD4 cell counts. The maximum parasitic isolation was in the patients whose CD4 cell counts were below 200 cells/μl.</p> <p>Conclusion</p> <p>There was an inverse relation between the CD4 counts and duration of diarrhea. <it>Cryptosporidium </it>spp. was isolated maximum among all the parasites in the HIV patients. The highest incidence of infection was seen in the rainy season.</p

Rituximab biosimilar RTXM83 versus reference rituximab in combination with CHOP as first-line treatment for diffuse large B-cell lymphoma: a randomized, double-blind study

This multicenter, double-blind, randomized study compared the efficacy, pharmacokinetics (PKs)/pharmacodynamics (PDs), safety and immunogenicity profile of RTXM83 vs. reference rituximab (R-rituximab), both with CHOP, as first-line treatment of diffuse large B-cell lymphoma (DLBCL). A total of 272 patients <65 years of age, with good prognosis (136 per arm) were randomized (1:1) to receive six cycles of either RTXM83 or R-rituximab. The primary efficacy endpoint was achieved (overall response rate of 83.6% for RTXM83 and 82.9% for R-rituximab) with a difference 0.7% between arms (95%CI: [-8.77% to 10.17%]) fulfilling the predefined non-inferiority margin (-13%). Similar number of patients reported at least one adverse event (AE) (131 per arm) or one serious AE (47 with RTXM83 and 45 with R-rituximab). Anti-drug antibody development was comparable between the arms. PK/PD secondary endpoint results support similarity between the compounds. RTXM83 exhibits non-inferior efficacy and similar safety/immunogenicity to R-rituximab, being an accessible alternative for the treatment of patients with previously untreated DLBCL

Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): An open-label, randomised, phase 3 trial

PubMed ID: 26822398Background: Trastuzumab resistance is a key therapeutic challenge in metastatic breast cancer. We postulated that broader inhibition of ErbB receptors with afatinib would improve clinical outcomes compared with HER2 inhibition alone in patients who had progressed on previous trastuzumab treatment. LUX-Breast 1 compared afatinib plus vinorelbine with trastuzumab plus vinorelbine for such patients with HER2-positive metastatic breast cancer. Methods: We did this open-label trial at 350 hospitals in 41 countries worldwide. We enrolled female patients with HER2-overexpressing metastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of metastatic disease with trastuzumab. Participants were randomly assigned (2:1) to receive oral afatinib (40 mg/day) plus intravenous vinorelbine (25 mg/m 2 per week) or intravenous trastuzumab (2 mg/kg per week after 4 mg/kg loading dose) plus vinorelbine. Randomisation was done centrally and stratified by previous trastuzumab treatment (adjuvant vs first-line treatment), hormone receptor status (oestrogen receptor and progesterone receptor positive vs others), and region. The primary endpoint was progression-free survival, assessed in the intention-to-treat population. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT01125566. Findings: Between Aug 26, 2010, and April 26, 2013, we enrolled 508 patients: 339 assigned to the afatinib group and 169 assigned to the trastuzumab group. Recruitment was stopped on April 26, 2013, after a benefit-risk assessment by the independent data monitoring committee was unfavourable for the afatinib group. Patients on afatinib plus vinorelbine had to switch to trastuzumab plus vinorelbine, afatinib monotherapy, vinorelbine monotherapy, or receive treatment outside of the trial. Median follow-up was 9·3 months (IQR 3·7-16·0). Median progression-free survival was 5·5 months (95% CI 5·4-5·6) in the afatinib group and 5·6 months (5·3-7·3) in the trastuzumab group (hazard ratio 1·10 95% CI 0·86-1·41; p=0·43). The most common drug-related adverse events of grade 3 or higher were neutropenia (190 [56%] of 337 patients in the afatinib group vs 102 [60%] of 169 patients in the trastuzumab group), leucopenia (64 [19%] vs 34 [20%]), and diarrhoea (60 [18%] vs none). Interpretation: Trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer who had progressed on trastuzumab. Funding: Boehringer Ingelheim. © 2016 Elsevier Ltd.Novartis AstraZeneca Boehringer Ingelheim Eisai KoreaWe showed that afatinib plus vinorelbine did not improve progression-free survival or objective response and was also associated with shorter overall survival compared with trastuzumab plus vinorelbine. Afatinib was also less well tolerated than was trastuzumab. Cross-signalling by other members of the ErbB family is thought to be an important mechanism through which HER2 can remain activated, despite HER2-targeted therapy. We therefore expected that broader inhibition of the ErbB family with afatinib might improve efficacy compared with trastuzumab in patients who were anticipated to have trastuzumab resistance (based on progression during or shortly after trastuzumab treatment). However, the results show that continuation of trastuzumab beyond progression conferred better outcomes than did switching to an ErbB family blocker. Our findings also suggest that the definition of trastuzumab resistance remains challenging. Despite progressing on or shortly after trastuzumab treatment, a proportion of patients may retain some sensitivity to this drug, which could have implications for future studies in this area. Our findings accord with those from studies of tyrosine kinase inhibitors for HER2-overexpressing metastatic breast cancer. In the MA.31 trial, 23 a taxane (paclitaxel or docetaxel) plus lapatinib was associated with shorter median progression-free survival than was a taxane plus trastuzumab for first-line treatment of metastatic breast cancer (9·0 months vs 11·3 months; HR 1·37 [95% CI 1·13–1·65]; p=0·001), resulting in early closure of the trial. Overall survival did not significantly differ between lapatinib plus taxane and trastuzumab plus taxane in the intention-to-treat group (HR 1·28 [95% CI 0·95–1·72]; p=0·11); however, overall survival was worse with lapatinib than with trastuzumab in patients with centrally confirmed HER2-positive disease (HR 1·47 [95% CI 1·03–2·09]; p=0·03). 23 In the CEREBEL trial, 24 median progression-free survival and overall survival were shorter with lapatinib plus capecitabine than with trastuzumab plus capecitabine in patients with HER2-positive metastatic breast cancer, although the difference was not significant for overall survival (progression-free survival was 6·6 months vs 8·1 months; HR 1·30 [95% CI 1·04–1·64]; p=0·021; overall survival was 22·7 months vs 27·3 months; HR 1·34 [95% CI 0·95–1·90]; p=0·095). In MA.31, roughly 40% of patients had a primary diagnosis of metastatic breast cancer and thus had not received any previous anti-HER2 treatment. By contrast, to our knowledge, our study is the first to compare trastuzumab-based treatment in multiple lines versus switching to an alternative treatment on progression. Furthermore, although MA.31 and CEREBEL assessed lapatinib (an EGFR and HER2 inhibitor), we used a second-generation irreversible ErbB family inhibitor to provide broader inhibition. By contrast with the CEREBEL trial, which included patients without brain metastases at baseline, our study enrolled those with inactive, asymptomatic brain metastases. In this small subgroup of patients, there was no evidence that switching to irreversible ErbB family inhibition was beneficial compared with remaining on trastuzumab-based therapy. Similarly, a retrospective subgroup analysis of EMILIA 25 showed that the rate of CNS progression was similar for patients receiving trastuzumab emtansine and those receiving lapatinib plus capecitabine. In the present study, the incidence of drug-related adverse events was consistent with the safety profiles of each drug; however afatinib plus vinorelbine was less well tolerated than was trastuzumab plus vinorelbine. More patients in the afatinib group than in the trastuzumab group had adverse events leading to treatment discontinuation, serious adverse events, and fatal adverse events. The incidence and severity of haematological adverse events (including neutropenia) were generally similar between treatment groups; however, more patients in the afatinib group had fatal infections than did those in the trastuzumab group. One potential explanation for poorer tolerability could be a negative pharmacological interaction between afatinib and vinorelbine. However, extensive investigation of the combination in phase 1 studies, 26,27 based on plasma exposure, did not suggest any pharmacokinetic interaction between these two compounds. LUX-Breast 1 was a large randomised multicentre trial; nevertheless, there were some limitations. First, recruitment was terminated early and patients receiving afatinib were required to switch to alternative treatments, which only enables an adequate comparison of efficacy and safety results between the randomised treatment groups up to the point of the treatment switch. The findings for overall survival could be affected by subsequent treatments, the data for which are still being collected, and many patients have still not had an overall survival event, which could render the findings immature. Additionally, second-generation antibodies, such as pertuzumab and trastuzumab emtansine (not available at the time of study design), are now standard treatments in many countries. As such, use of trastuzumab across multiple lines or trastuzumab plus vinorelbine as first-line treatment is limited in clinical practice. However, trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer failing on trastuzumab. Contributors NH, C-SH, ZS, R-GG, MU-F, BX, and MP-G designed the study. NH, C-SH, SH, D-CY, KHJ, KS, JR, Y-HI, MW, QS, and BX recruited patients. NH, C-SH, SH, D-CY, ZS, S-AI, KHJ, KS, JR, JJ, QZ, Y-HI, MW, QS, S-CC, MU-F, BX, and MP-G collected data. NH, C-SH, SH, S-AI, KHJ, JR, JJ, QZ, Y-HI, S-CC, R-GG, MU-F, and BX analysed and interpreted data. MU-F provided administrative and technical support. All authors drafted and reviewed the report, and approved the final version for submission. Declaration of interests NH has received research fees to her institution for conducting studies from Boehringer Ingelheim; and personal fees from Roche and Novartis. C-SH has received grants from Boehringer Ingelheim and Roche. SH has received research funds to her institution from Boehringer Ingelheim, Genentech/Roche, Novartis, Lilly, OBI Pharmaceuticals, Merrimack, PUMA, Biomarin, GlaxoSmithKline, and Amgen; personal fees for reimbursement for travel to meetings from Boehringer Ingelheim, Genentech/Roche, Novartis, Lilly, OBI Pharmaceuticals, and Merrimack; honoraria for leading an advisory board from Boehringer Ingelheim; and honoraria for speaking at a conference from Genentech/Roche. S-AI has received research funding from AstraZeneca and has participated in advisory boards for AstraZeneca, Novartis, and Roche. KHJ has received a grant from Eisai Korea. JJ has held an advisory role with Boehringer Ingelheim. R-GG and MU-F are employees of Boehringer Ingelheim. The other authors declare no competing interests. Acknowledgments This study was supported by Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. We thank the patients, their families, and all of the investigators who participated in this study. Additionally, we thank the Boehringer Ingelheim trial manager Annick Lahogue for her excellent support throughout the trial. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Caroline Allinson of GeoMed, an Ashfield company, part of UDG Healthcare, during the preparation of this Article. -