Primary resistance to selpercatinib in a patient with advanced medullary thyroid cancer.

Selpercatinib, a selective RET kinase inhibitor, has demonstrated remarkable efficacy in treating patients with advanced medullary (MTC) and differentiated thyroid cancer with RET alterations. Primary resistance to selpercatinib is a very uncommon situation, and its underlying mechanisms are poorly understood. We report the case of a 42-year-old female with advanced MTC harboring a somatic M918T RET mutation who exhibited a primary resistance to selpercatinib. Despite prompt treatment initiation after the diagnosis of progressive disease, the patient continued experiencing rapid spread of disease, characterized by the appearance of new metastatic lesions and increased tumor burden. Genomic analysis revealed no additional mutations associated with on-target or off-target resistance. This case highlights a rare clinical scenario of primary resistance to selpercatinib in advanced MTC. While secondary resistance mechanisms have been well-documented, primary resistance remains poorly understood. Possible explanations include tumor heterogeneity and activation of alternative signaling pathways that stills need to be elucidated. Emerging therapies targeting resistance mechanisms and next-generation RET inhibitors offer promising avenues for further investigation.

Genetic diversity and primary drug resistance transmission in Mycobacterium tuberculosis in southern Mexico.

Tuberculosis is a global human health threat, especially in developing countries. The present study aimed to describe the genetic diversity of Mycobacterium tuberculosis and to measure the transmission rates of primary and acquired resistance. A total of 755 M. tuberculosis isolates from a cohort study of patients with culture-confirmed pulmonary tuberculosis in Orizaba, Veracruz, performed between 1995 and 2010 were genotyped by the 24-locus mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR) method. Drug susceptibility was determined. Logistic regression models were constructed to identify the variables associated with resistance and clusters. The recent transmission index (RTI), the Hunter-Gaston discrimination index (HGDI) for the MIRU-VNTR test and allelic diversity (h) were calculated. The Haarlem and LAM lineages were the most common in the population. A total of 519 isolates were grouped into 128 clusters. The overall drug resistance rate was 19%, isoniazid monoresistance (10%) was the most common, and 3.4% of the isolates were multidrug resistant. Among the 116 isolates resistant to at least one drug, the primary and acquired resistance rates were 81.9% and 18.1%, respectively. Primary resistance was associated with belonging to a cluster (aOR 4.05, 95% CI 1.5-11.2, p = 0.007). Previous treatment history (aOR 9.05, 95% CI 3.6-22.5, p < 0.001) and LAM lineage (aOR 4.25, 95% CI 1.4-12.7, p = 0.010) were associated with multidrug-resistant tuberculosis (MDR-TB). The RTI was 51.7%, and the 24-locus MIRU-VNTR HGDI was 0.98. The alleles with the greatest diversity were 4056-QUB26 (h = 0.84), 2163b-QUB11b (h = 0.79), and 424-Mtub04 (h = 0.72). Primary resistance transmission, high LAM lineage prevalence and its association with MDR-TB represent public health problems. The implementation of molecular tools is needed to improve the existing control surveillance tuberculosis program.

Emergence and Transmission of Drug-/Multidrug-resistant Mycobacterium leprae in a Former Leprosy Colony in the Brazilian Amazon.

BACKGROUND: Leprosy has been treated with multidrug therapy, which has been distributed for free across the globe and regarded as highly efficient. However, the impossibility of growing Mycobacterium leprae in axenic media has historically impaired assessments of M. leprae resistance, a parameter only recently detectable through molecular methods. METHODS: A systematic, population-based search for M. leprae resistance in suspected leprosy relapse cases and contacts was performed in Prata Village, an isolated, hyperendemic, former leprosy colony located in the Brazilian Amazon. Results led to an extended active search involving the entire Prata population. Confirmed leprosy cases were investigated for bacterial resistance using a combination of in vivo testing and direct sequencing of resistance genes folP1, rpoB, and gyrA. A molecular epidemiology analysis was performed using data from 17 variable number tandem repeats (VNTR). RESULTS: Mycobacterium leprae was obtained from biopsies of 37 leprosy cases (18 relapses and 19 new cases): 16 (43.24%) displayed drug-resistance variants. Multidrug resistance to rifampicin and dapsone was observed in 8 relapses and 4 new cases. Single resistance to rifampicin was detected in 1 new case. Resistance to dapsone was present in 2 relapses and 1 new case. Combined molecular resistance and VNTR data revealed evidence of intra-familial primary transmission of resistant M. leprae. CONCLUSIONS: A comprehensive, population-based systematic approach to investigate M. leprae resistance in a unique population revealed an alarming scenario of the emergence and transmission of resistant strains. These findings may be used for the development of new strategies for surveillance of drug resistance in other populations.

Emergence and transmission of drug-/multidrug-resistant Mycobacterium leprae in a former leprosy colony in the Brazilian Amazon

BACKGROUND: Leprosy has been treated with multidrug therapy (MDT) distributed for free across the globe and regarded as highly efficient. However, the impossibility to grow M. leprae in axenic media has historically impaired assessment of M. leprae resistance, a parameter only recently detectable through molecular methods. METHODS: A systematic, population-based search for M. leprae resistance in suspected leprosy relapse cases and contacts was performed in Prata Village, an isolated, hyper-endemic former leprosy colony located in the Brazilian Amazon. Results led to an extended active search involving the entire Prata population. Confirmed leprosy cases were investigated for bacterial resistance using a combination of in vivo testing and direct sequencing of resistance genes folP1, rpoB and gyrA. Molecular epidemiology analysis was performed using data from 17 variable number tandem repeats (VNTR). RESULTS: M. leprae was obtained from biopsies of 37 leprosy cases (18 relapses and 19 new); 16 (43.24%) displayed drug-resistance variants. Multi-drug resistance to rifampicin and dapsone was observed in 8 relapses and 4 new cases. Single resistance to rifampicin was detected in one new case. Resistance to dapsone was present in two relapses and one new case. Combined molecular resistance and VNTR data revealed evidence of intra-familial primary transmission of resistant M. leprae. CONCLUSIONS: A comprehensive, population-based systematic approach to investigate M. leprae resistance in a unique population revealed an alarming scenario of emergence and transmission of resistant strains. These findings may be used for the development of new strategies for surveillance of drug resistance in other populations.

Nuevos retos en el tratamiento de la infección por helicobacter pylori / New challenges in the treatment of the infection for helicobacter pylori

RESUMEN La infección por helicobacter pylori afecta aproximadamente al 50% de la población mundial, es causante de gastritis crónica, úlcera péptica, cáncer gástrico y linfoma del tejido linfoide asociado a la mucosa. Desde su descubrimiento, la erradicación ha sido uno de los más importantes retos en Gastroenterología. En muchos países se desconoce la prevalencia de resistencia primaria del microorganismo a los diferentes antibióticos que empíricamente se utilizan, y por no realizar pruebas de rutina que verifican su erradicación en la práctica diaria, se ignora la efectividad de los esquemas prescritos. El incremento progresivo de la resistencia a la claritromicina y metronidazol, unido a una ausencia de antibioticoterapia alternativa, desafía la capacidad para eliminar de manera efectiva a ésta bacteria. El subcitrato de bismuto ha resurgido y su adición en la terapia ha permitido aumentar las tasas de curación por encima del 90%. Actualmente se invoca que para mejorar la eficacia en el tratamiento se debe combinar una supresión potente del ácido gástrico en tratamientos combinados cuádruples con una duración de 14 días, para la mayoría de los casos. La adherencia al tratamiento es crucial para obtener buenos resultados terapéuticos.

ABSTRACT The infection for helicobacter pylori affects approximately to the world population's 50%, it is causing of chronic gastritis, peptic ulcer, gastric cancer and linfoma associated to the mucous one. From their discovery, the eradication has been one of the most important challenges in Gastroenterología. In many countries the prevalencia of primary resistance is ignored from the microorganism to the different antibiotics that empirically they are used, and for not carrying out routine tests that verify its eradication in the daily practice, the effectiveness of the prescribed outlines it is ignored. The progressive increment of the resistance to the claritromicina and metronidazol, together to an absence of alternative antibioticotherapy, challenges the capacity to eliminate from an effective way to this bacteria. The bismuth subcitrato has resurged and its addition in the therapy has allowed to increase the cure rates above 90%. At the moment it is invoked that to improve the effectiveness in the treatment, that is should combine a potent suppression of the gastric acid in combined quadruple treatments with a duration of 14 days, for most of the cases. The adherence to the treatment is crucial to obtain therapeutic good results.

Transmitted drug resistance in patients with acute/recent HIV infection in Brazil

Abstract Introduction: The widespread use of antiretroviral therapy increased the transmission of antiretroviral resistant HIV strains. Antiretroviral therapy initiation during acute/recent HIV infection limits HIV reservoirs and improves immune response in HIV infected individuals. Transmitted drug resistance may jeopardize the early goals of early antiretroviral treatment among acute/recent HIV infected patients. Methods: Patients with acute/recent HIV infection who underwent resistance test before antiretroviral treatment initiation were included in this analysis. HIV-1 sequences were obtained using an in house protease/reverse transcriptase genotyping assay. Transmitted drug resistance was identified according to the Stanford HIV Database for Transmitted Drug Resistance Mutations, based on WHO 2009 surveillance list, and HIV-1 subtyping according to Rega HIV-1 subtyping tool. Comparison between patients with and without transmitted drug resistance was made using Kruskal-Wallis and Chi-square tests. Results: Forty-three patients were included, 13 with acute HIV infection and 30 with recent HIV infection. The overall transmitted drug resistance prevalence was 16.3% (95% confidence interval [CI]: 8.1-30.0%). The highest prevalence of resistance (11.6%, 95% CI: 8.1-24.5) was against non-nucleoside reverse transcriptase inhibitors, and K103N was the most frequently identified mutation. Conclusions: The high prevalence of nonnucleoside reverse transcriptase inhibitors resistance indicates that efavirenz-based regimen without prior resistance testing is not ideal for acutely/recently HIV-infected individuals in our setting. In this context, the recent proposal of including integrase inhibitors as a first line regimen in Brazil could be an advantage for the treatment of newly HIV infected individuals. However, it also poses a new challenge, since integrase resistance test is not routinely performed for antiretroviral naive individuals. Further studies on transmitted drug resistance among acutely/recently HIV-infected are needed to inform the predictors of transmitted resistance and the antiretroviral therapy outcomes among these population.

Transmitted drug resistance in patients with acute/recent HIV infection in Brazil.

INTRODUCTION: The widespread use of antiretroviral therapy increased the transmission of antiretroviral resistant HIV strains. Antiretroviral therapy initiation during acute/recent HIV infection limits HIV reservoirs and improves immune response in HIV infected individuals. Transmitted drug resistance may jeopardize the early goals of early antiretroviral treatment among acute/recent HIV infected patients. METHODS: Patients with acute/recent HIV infection who underwent resistance test before antiretroviral treatment initiation were included in this analysis. HIV-1 sequences were obtained using an in house protease/reverse transcriptase genotyping assay. Transmitted drug resistance was identified according to the Stanford HIV Database for Transmitted Drug Resistance Mutations, based on WHO 2009 surveillance list, and HIV-1 subtyping according to Rega HIV-1 subtyping tool. Comparison between patients with and without transmitted drug resistance was made using Kruskal-Wallis and Chi-square tests. RESULTS: Forty-three patients were included, 13 with acute HIV infection and 30 with recent HIV infection. The overall transmitted drug resistance prevalence was 16.3% (95% confidence interval [CI]: 8.1-30.0%). The highest prevalence of resistance (11.6%, 95% CI: 8.1-24.5) was against non-nucleoside reverse transcriptase inhibitors, and K103N was the most frequently identified mutation. CONCLUSIONS: The high prevalence of nonnucleoside reverse transcriptase inhibitors resistance indicates that efavirenz-based regimen without prior resistance testing is not ideal for acutely/recently HIV-infected individuals in our setting. In this context, the recent proposal of including integrase inhibitors as a first line regimen in Brazil could be an advantage for the treatment of newly HIV infected individuals. However, it also poses a new challenge, since integrase resistance test is not routinely performed for antiretroviral naive individuals. Further studies on transmitted drug resistance among acutely/recently HIV-infected are needed to inform the predictors of transmitted resistance and the antiretroviral therapy outcomes among these population.

Investigation by the Method of INNO-LiPA of Primary Resistance to Lamivudine in Patients with Chronic Hepatitis B Who Have Not Used Antiviral Therapy.

AIM: Two billion people around the world are exposed to the hepatitis B virus (HBV) and about 350 million are infected with chronic HBV. The infection can be acquired early (neonatal) and becomes chronic in 90%; this rate reduces to 30% between ages one and five years. There is a 25% risk of chronicity in adults. Nowadays, immunomodulatory and antiviral pegylated-interferons or oral antiviral agents are used in the treatment of chronic hepatitis B. Lamivudine is an effective oral antiviral agent which inhibits the replication of HVB by blocking reverse transcriptase enzyme. The study aims to detect the resistance of HBV to lamivudine in the community and evaluate the effectiveness and suitability of early treatment with lamivudine. SUBJECTS AND METHODS: One hundred patients who presented to our Faculty of Medicine Hospital Infectious Diseases and Clinical Microbiology Department and had not received any antiviral treatment were recruited. The INNO-LiPA method was applied to investigate primary lamivudine resistance in patients. RESULTS: Seventy-eight patients were HBeAg-negative and 22 patients were HBeAg-positive. A statistically significant correlation was found between HBeAg positivity, alanine aminotransferase (ALT) elevation and HBV DNA (p < 0.05). The rtM204V and L180M mutation motif was found in one patient with HBeAg positivity. CONCLUSIONS: Hepatitis B virus in our region is not a lamivudine-resistant strain and early treatment with lamivudine is an effective and convenient method.

Genetic diversity and primary resistance among HIV-1-positive patients from Maringá, Paraná, Brazil / Diversidade genética e resistência primária entre pacientes HIV-1-positivos de Maringá, Paraná, Brasil

The objective of this study is to identify subtypes of Human Immunodeficiency Virus type 1 (HIV-1) and to analyze the presence of mutations associated to antiretroviral resistance in the protease (PR) and reverse transcriptase (RT) regions from 48 HIV-1 positive treatment naïve patients from an outpatient clinic in Maringá, Paraná, Brazil. Sequencing was conducted using PR, partial RT and group-specific antigen gene (gag) nested PCR products from retrotranscribed RNA. Transmitted resistance was determined according to the Surveillance Drug Resistance Mutation List (SDRM) algorithm. Phylogenetic and SimPlot analysis of concatenated genetic segments classified sequences as subtype B 19/48 (39.6%), subtype C 12/48 (25%), subtype F 4/48 (8.3%), with 13/48 (27.1%) recombinant forms. Most recombinant forms were B mosaics (B/F 12.5%, B/C 10.4%), with one C/F (2.1%) and one complex B/C/F mosaic (2.1%). Low levels of transmitted resistance were found in this study, 2/48 (2.1% to NRTIs and 2.1% for PI). This preliminary data may subsidize the monitoring of the HIV evolution in the region.

O objetivo foi identificar subtipos do Vírus da Imunodeficiência Humana tipo-1 (HIV-1) e analisar a presença de mutações/polimorfismos nas regiões da protease (PR) e transcriptase reversa (TR) de 48 pacientes virgens de tratamento atendidos no município de Maringá, Paraná, Brasil. O sequenciamento foi conduzido usando produtos de nested PCR dos genes da PR, TR parcial e group-specific antigen gene (gag) de RNA retrotranscrito. A interpretação da resistência transmitida foi realizada segundo o algoritmo Surveillance Drug Resistance Mutation List (SDRM). As análises filogenética e SimPlot dos segmentos concatenados classificaram as sequências como subtipo B 19/48 (39,6%), subtipo C 12/48 (25%), subtipo F 4/48 (8,3%), com 13/48 (27,1%) formas recombinantes. A maioria das formas recombinantes era mosaicos B (B/F 12,5%, B/C 10,4%), com um C/F (2,1%) e um mosaico complexo B/C/F (2,1%). A prevalência de resistência transmitida foi de 4,2% (2,1% para ITRN e 2,1% para IP). Baixos níveis de resistência transmitida foram encontrados nesse estudo, 2/48 (2,1% para INTR e 2,1% para IP). Esses achados, embora preliminares, podem contribuir no monitoramento da epidemia de HIV na região.

Helicobacter pylori: Tratamiento actual. Un importante reto en gastroenterología / Helicobacter pylori: Current treatment An importanmt challenge for gastroenterology

Desde cuando se descubrió Helicobacter pylori, su erradicación ha constituido uno de los más importantes retos en gastroenterología. En muchas partes se desconocen las prevalencias de resistencia primaria del microorganismo a los diferentes antibióticos que empíricamente utilizan y por no realizar de rutina pruebas para verificar la erradicación, en la práctica diaria, se ignora la efectividad de los esquemas prescritos. Conocer estos dos factores, permite, no solo identificar los que aún persisten infectados, sino también elegir la próxima terapia de rescate de una manera más racional. El no disponer de la información sobre resistencia pretratamiento es un inconveniente que impide evaluar el impacto de la resistencia con el fracaso terapéutico. A nivel mundial, la triple terapia estándar ha perdido la eficacia que tenía en el pasado y la terapia secuencial no es igualmente eficaz en todos los sitios, en especial en regiones en donde existe alta resistencia a claritromicina y metronidazol. Los esquemas con levofloxacina han demostrado eficacia en triples terapias de primera línea o como terapia de rescate, pero es necesario que cada región adopte sus propios esquemas de tratamiento fundamentados en pruebas de susceptibilidad y en estudios farmacogenómicos.

Since when Helicobacter pylori was discovered, the eradication has been one of the most important challenges in gastroenterology. In many places, the prevalence of primary resistance of microorganism to the different antibiotics is not known, and these are used empirically. In daily practice, no routine test is used to verify the eradication, and therefore do not know the effectiveness of the schemes. Knowing these two factors is possible identify those still infected and choose the next rescue therapy in a rational form. The absence of information on pre-treatment resistance is a problem that cannot measure the impact of resistance to therapeutic failure. A global level, the standard triple therapy has lost the effectiveness that it had in the past and sequential therapy is not equally effective everywhere, especially in regions where there is high resistance to clarithromycin and metronidazole. The schemes have proved effective with levofloxacin triple therapies as first line therapy or rescue, but it is necessary that each region takes its own schemes of treatment based on susceptibility tests and pharmacogenomic studies.