The impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs.

Background: In South Africa, an estimated 11% of the population have high alcohol use, a major risk factor for TB. Alcohol and other substance use are also associated with poor treatment response, with a potential mechanism being altered TB drug pharmacokinetics.

Objectives: To investigate the impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs in participants with pulmonary TB.

High-Dose Isoniazid Lacks EARLY Bactericidal Activity against Isoniazid-resistant Tuberculosis Mediated by katG Mutations: A Randomized Phase II Clinical Trial.

Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis. However, its activity against () with mutations (which typically confer high-level resistance) is not established. To characterize the early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by -mutated .

Pharmacokinetics and Safety of Twice-daily Ritonavir-boosted Atazanavir With Rifampicin.

Background: Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin.

Methods: DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with human immunodeficiency virus (HIV) on atazanavir/ritonavir-based antiretroviral therapy (ART) in Uganda.

Dolutegravir pharmacokinetics in Ugandan patients with TB and HIV receiving standard- versus high-dose rifampicin.

Higher rifampicin doses may improve tuberculosis treatment outcomes. This could however exacerbate the existing drug interaction with dolutegravir. Moreover, the metabolism of dolutegravir may also be affected by polymorphism of a gene that codes for uridine diphosphate glucuronosyltransferase.

Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin.

We characterized the pharmacokinetics of standard- and high-dose rifampicin in Ugandan adults with tuberculosis and HIV taking dolutegravir- or efavirenz-based antiretroviral therapy. A liver model with saturable hepatic extraction adequately described the data, and the increase in exposure between high and standard doses was 4.7-fold.

Decreased Dolutegravir and Efavirenz Concentrations With Preserved Virological Suppression in Patients With Tuberculosis and Human Immunodeficiency Virus Receiving High-Dose Rifampicin.

Background: Higher doses of rifampicin may improve treatment outcomes and reduce the duration of tuberculosis (TB) therapy. However, drug-drug interactions with antiretroviral therapy (ART) and safety in people with human immunodeficiency virus (HIV) have not been evaluated.

Methods: This was a randomized, open-label trial where newly diagnosed TB patients were randomized to higher (35 mg/kg) or standard (10 mg/kg) daily-dose rifampicin.

Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis.

Background: The WHO-endorsed shorter-course regimen for MDR-TB includes high-dose isoniazid. The pharmacokinetics of high-dose isoniazid within MDR-TB regimens has not been well described.

Objectives: To characterize isoniazid pharmacokinetics at 5-15 mg/kg as monotherapy or as part of the MDR-TB treatment regimen.

Bedaquiline exposure in pregnancy and breastfeeding in women with rifampicin-resistant tuberculosis.

Aims: We aimed to explore the effect of pregnancy on bedaquiline pharmacokinetics (PK) and describe bedaquiline exposure in the breast milk of mothers treated for rifampicin-resistant tuberculosis (TB), where there are no human data available.

Methods: We performed a longitudinal PK study in pregnant women treated for rifampicin-resistant TB to explore the effect of pregnancy on bedaquiline exposure. Pharmacokinetic sampling was performed at 4 time-points over 6 hours in the third trimester, and again at approximately 6 weeks postpartum.

Population Pharmacokinetics of Antimalarial Naphthoquine in Combination with Artemisinin in Tanzanian Children and Adults: Dose Optimization.

The combination antimalarial therapy of artemisinin-naphthoquine (ART-NQ) was developed as a single-dose therapy, aiming to improve adherence relative to the multiday schedules of other artemisinin combination therapies. The pharmacokinetics of ART-NQ has not been well characterized, especially in children. A pharmacokinetic study was conducted in adults and children over 5 years of age (6 to 10, 11 to 17, and ≥18 years of age) with uncomplicated malaria in Tanzania.

A Semimechanistic Model of the Bactericidal Activity of High-Dose Isoniazid against Multidrug-Resistant Tuberculosis: Results from a Randomized Clinical Trial.

There is accumulating evidence that higher-than-standard doses of isoniazid are effective against low-to-intermediate-level isoniazid-resistant strains of , but the optimal dose remains unknown. To characterize the association between isoniazid pharmacokinetics (standard or high dose) and early bactericidal activity against (drug sensitive and inhA mutated) and status. ACTG (AIDS Clinical Trial Group) A5312/INHindsight is a 7-day early bactericidal activity study with isoniazid at a normal dose (5 mg/kg) for patients with drug-sensitive bacteria and 5, 10, and 15 mg/kg doses for patients with mutants.

Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits.

SQ109 is a novel well-tolerated drug candidate in clinical development for the treatment of drug-resistant tuberculosis (TB). It is the only inhibitor of the MmpL3 mycolic acid transporter in clinical development. No SQ109-resistant mutant has been directly isolated thus far , in mice, or in patients, which is tentatively attributed to its multiple targets.

Pharmacokinetics and Drug-Drug Interactions of Isoniazid and Efavirenz in Pregnant Women Living With HIV in High TB Incidence Settings: Importance of Genotyping.

The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well-described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug interactions between isoniazid and efavirenz in pregnant women.

Effects of Pregnancy and Isoniazid Preventive Therapy on Mycobacterium tuberculosis Interferon Gamma Response Assays in Women With HIV.

Background: Pregnancy is accompanied by immune suppression. We hypothesized that Mycobacterium tuberculosis-specific inflammatory responses used to identify latent tuberculosis infection (LTBI) lose positivity during pregnancy. We also hypothesized that isoniazid preventive therapy (IPT) may revert LTBI diagnoses because of its sterilizing activity.

The Effect of Frequent Exposure to , HIV-Infection and Other Co-Morbidities on Development of Severe Malaria in Malawian Adults.

Aim: malaria predominantly affects children residing in endemic areas. However, recently a significant number of Malawian adults, who otherwise should have attained some malaria-specific immunity, have been observed to succumb to either uncomplicated malaria (UM) or severe malaria (SM). In addition, it is still unknown whether HIV is a contributing factor to SM in Malawian non-pregnant adults.

HIV infection has a profound effect on hematological factors but not on electrolyte profile of Malawian adults presenting with uncomplicated malaria and severe malaria.

Aim: Although malaria and HIV infections independently affect the electrolyte and hematologic profiles, little is known of how these profiles are affected in individuals coinfected with malaria and HIV. We therefore conducted this study to investigate the electrolyte and hematologic profiles of Malawian adults presenting with either uncomplicated malaria (UM), severe malaria (SM), and those presenting with HIV and UM or HIV and SM.

Methods: Study participants were recruited at Queen Elizabeth Central Hospital, and malaria infection was confirmed by rapid diagnostic test and malaria slides, and full blood count, HIV, and wet chemistries were analyzed.