Hepatotoxicity and tuberculosis treatment outcomes in chronic liver disease.

Background: The treatment of tuberculosis (TB) is known to cause liver injury, however, there is limited data to guide optimal treatment for patients with chronic liver disease. Methods: We undertook a retrospective case series of patients with chronic liver disease and TB disease. The primary objective was to determine if there was a difference in the incidence of drug-induced liver injury (DILI) in patients with cirrhosis versus those with chronic hepatitis. Additionally, we sought to compare TB treatment outcomes, type and duration of therapy, and incidence of adverse events. Results: We included 56 patients (chronic hepatitis 40; cirrhosis 16). There were 33 patients (58.9%) who experienced DILI requiring treatment modification, with no significant difference between groups (65% versus 43.8%, p = 0.23). Patients with chronic hepatitis were more likely to receive treatment with standard first-line intensive phase therapy that included a combination of rifampin (RIF), isoniazid, and pyrazinamide (80.8% versus 19.2%, p = 0.03) and any regimen than included isoniazid (92.5% versus 68.8%, p = 0.04). The risk of DILI was higher when more hepatotoxic TB medications were used. Overall treatment success in this cohort was low (55.4%), with no significant difference between groups (62.5% versus 37.5%, p = 0.14). Most patients with treatment success (97%) were able to tolerate a rifamycin. Conclusions: The risk of DILI is high, especially with the use of isoniazid, in patients with TB and chronic liver disease. This risk can be effectively mitigated with no difference in treatment outcomes in the presence of cirrhosis.

Historique: Il est bien connu que le traitement de la tuberculose (TB) provoque des lésions hépatiques, mais les données sont limitées pour orienter le traitement des patients atteints d'une hépatopathie chronique. Méthodologie: Les chercheurs ont étudié une série rétrospective de cas de patients atteints d'une hépathopathie chronique et d'une TB. Ils s'étaient donné comme objectif primaire de déterminer s'il y avait une différence entre l'incidence de lésion hépatique d'origine médicamenteuse (LHOM) chez les patients atteints d'une cirrhose et ceux atteints d'une hépatite chronique. De plus, ils ont comparé les résultats des traitements de la TB, le type et la durée du traitement et l'incidence d'événements indésirables. Résultats: Les chercheurs ont inclus 56 patients (hépatite chronique : 40; cirrhose : 16). De ce nombre, 33 (58,9 %) avaient présenté une LHOM ayant suscité une modification au traitement, sans différence notable entre les groupes : 65 % par rapport à 43,8 %, p = 0,23. Les patients atteints d'hépatite chronique étaient plus susceptibles de recevoir un traitement intensif standard en première ligne qui incluait une combinaison de rifampine (RIF), d'isoniazide et de pyrazinamide (80,8 % par rapport à 19,2 %, p = 0,03) ou une posologie qui comprenait de l'isoniazide (92,5 % par rapport à 68,8 %, p = 0,04). Le risque de LHOM était plus élevé lors de l'utilisation de médicaments contre la TB plus hépatotoxiques. La réussite globale du traitement était faible au sein de cette cohorte (55,4 %) et n'entraînait pas de différence significative entre les groupes (62,5 % par rapport à 37,5 %, p = 0,14). La plupart des patients dont le traitement était efficace (97 %) toléraient la rifamycine. Conclusions: Le risque de LHOM est élevé chez les patients atteints de TB et d'hépatopathie chronique, particulièrement lors de l'utilisation d'isoniazide. En présence de cirrhose, il est possible de l'atténuer avec efficacité sans modifier l'issue du traitement.

Costs of Tuberculosis at 3 Treatment Centers, Canada, 2010-2016.

We estimated costs of managing different forms of tuberculosis (TB) across Canada by conducting a retrospective chart review and cost assessment of patients treated for TB infection, drug-susceptible TB (DS TB), isoniazid-resistant TB, or multidrug-resistant TB (MDR TB) at 3 treatment centers. We included 90 patients each with TB infection and DS TB, 71 with isoniazid-resistant TB, and 62 with MDR TB. Median per-patient costs for TB infection (in 2020 Canadian dollars) were $804 (interquartile range [IQR] $587-$1,205), for DS TB $12,148 (IQR $4,388-$24,842), for isoniazid-resistant TB $19,319 (IQR $7,117-$41,318), and for MDR TB $119,014 (IQR $80,642-$164,015). Compared with costs for managing DS TB, costs were 11.1 (95% CI 9.1-14.3) times lower for TB infection, 1.7 (95% CI 1.3-2.1) times higher for isoniazid-resistant TB, and 8.1 (95% CI 6.1-10.6) times higher for MDR TB. Broadened TB infection treatment could avert high costs associated with managing TB disease.

Molecular Characterization of an SV Capture Site in the Mid-Region of the Presynaptic CaV2.1 Calcium Channel C-Terminal.

Neurotransmitter is released from presynaptic nerve terminals at fast-transmitting synapses by the action potential-gating of voltage dependent calcium channels (CaV), primarily of the CaV2.1 and CaV2.2 types. Entering Ca2+ diffuses to a nearby calcium sensor associated with a docked synaptic vesicle (SV) and initiates its fusion and discharge. Our previous findings that single CaVs can gate SV fusion argued for one or more tethers linking CaVs to docked SVs but the molecular nature of these tethers have not been established. We recently developed a cell-free, in vitro biochemical assay, termed SV pull-down (SV-PD), to test for SV binding proteins and used this to demonstrate that CaV2.2 or the distal third of its C-terminal can capture SVs. In subsequent reports we identified the binding site and characterized an SV binding motif. In this study, we set out to test if a similar SV-binding mechanism exists in the primary presynaptic channel type, CaV2.1. We cloned the chick variant of this channel and to our surprise found that it lacked the terminal third of the C-terminal, ruling out direct correlation with CaV2.2. We used SV-PD to identify an SV binding site in the distal half of the CaV2.1 C-terminal, a region that corresponds to the central third of the CaV2.2 C-terminal. Mutant fusion proteins combined with motif-blocking peptide strategies identified two domains that could account for SV binding; one in an alternatively spliced region (E44) and a second more distal site. Our findings provide a molecular basis for CaV2.1 SV binding that can account for recent evidence of C-terminal-dependent transmitter release modulation and that may contribute to SV tethering within the CaV2.1 single channel Ca2+ domain.