As a writer coming of age both personally and professionally during the early years of the HIV crisis I remain curious about our relative amnesia or short attention spans for the hard-won lessons learned during a pivotal time in clinical science.
The most powerful patient advocacy in the world drove the positive outcomes and clinical successes most of us take for granted. The leading edge of the science existed at the front line--well before long-term outcomes in efficacy and safety were established. I don't want to ruin your morning but dear reader, "safety" is not even a scientific term.
Because of the "interesting" evolution of the Food And Drug Administration (FDA)--and you definitely should read up on how we landed where we are today--and how gaps persist where real science can occur (The Cure in The Code: How 20th Century Law is Undermining 21st Century Medicine)--we are forgetting, at our own detriment, how off-label prescribing, critical thinking, and physician/clinical scientist group-think led to Euresist. The development of an international computer-based clinical management of antiretroviral drug resistance informed providers about what to do if a patient's viral load--once suppressed--escalated. What therapy or cocktail has proven effective?
The evolution of EuResist provided a tool for physicians to make evidence-based decisions (even if evidence was still evolving at the clinical level) at the point of care outside the government process that had proven to cumbersome to respond to the scale of morbidity and mortality.
EuResist Network is a partnership of eighteen institutions in Europe and beyond, which promotes and coordinates joint research and dissemination efforts of its partners.
- the EuResist Integrated Data Base (EIDB), among the largest available databases of HIV genotypes and clinical response to antiretroviral therapy, with more than 66.000 patients
- the EuResist treatment response prediction engine. The EuResist prediction engine is a data-driven system which predicts the response to combination drug therapy for a patient with a given viral genotype. The engine has an overall accuracy of around 77% which compares favourably with existing rules-based state-of-the-art systems such as HIVdb, ANRS, REGA.
- the EuResist Satellite DB (EsaDB), a tool for management of HIV patients data running locally on a PC. ESaDB is provided for free
I am not tossing babies out with volumes of bathwater--but seriously--where is the framework for a free open-sourced group think? I know there are pockets of sharing. I have written about them here. The model of for-profit data outpaces the network open-source solutions. Huge databases are amassed with partnerships boasting genetic libraries, claims data, clinical trial data and real world data--for a fee. A whopping fee with no promise of relevance or operational insights.
What is the solution? Provide context and conceptual understanding so healthcare providers can group-think knowing they have actionable data. An ever increasing number of immune-oncology (I/O) therapies are being granted break-through designations. I am excited to hear the latest data from larotrectinib, a novel selective TRK tyrosine kinase inhibitor (TKI). The high response rate is intriguing.
What do findings mean? Real world data is generated one patient at a time. It is up to us to assess real world evidence and share the narrative. It will be the providers at the point of care evaluating tumor genetics, micro-environments, mutational attributes of exomes, neoantigens, cell-cell signals of kinase pathways, and more as 'n of 1' findings outnumber epidemiological population estimations.
Despite durable responses to TRK kinase-directed therapy in patients with NTRK-rearranged
tumors, it is expected that acquired resistance to therapy will ultimately emerge in most patients.
Consistent with this expectation, previous reports have described the acquisition of secondary
mutations in the TRK kinase domain after treatment with entrectinib, a multi-kinase inhibitor with
activity against TRK, in two patients. Specifically, TRKA G595R and G667C substitutions were
identified in independent resistant clones from a patient with LMNA-NTRK1 fusion-positive
colorectal cancer; and a TRKC G623R substitution (homologous to TRKA G595R) was
identified in a patient with ETV6-NTRK3 fusion-positive mammary analogue secretory
carcinoma.--A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors
Stay-tuned for findings from the LOXO webcast scheduled June 4th...