Pharmacometric modelling to inform and improve TB and HIV treatment: Focus on drug-drug interactions and neglected populations

The global scale-up of tuberculosis treatment administered with antiretroviral therapy (ART) is the primary contributor to the 11 million averted deaths among individuals living with HIV observed between 2000 and 2019 in adults and children. Unfortunately, not all patients in need could fully benefit from these recent improvements in treatment because neglected populations are often excluded from clinical trials, including pregnant and breastfeeding women, children, adolescents, those with co-morbidities requiring additional drug treatments, and those with drug-resistant strains. This leaves many unanswered questions surrounding the management of TB, HIV, and TB/HIV in these vulnerable subpopulations. In this thesis, we utilise population pharmacokinetics and pharmacodynamic modelling to improve TB and HIV treatment in neglected populations using data from patients with TB or/and HIV. We analyse the pharmacogenomics, pharmacokinetics, and drug-drug interaction of efavirenz, isoniazid, and bedaquiline in pregnant women and characterise the pharmacokinetics and pharmacodynamics of high dose isoniazid in adults with multidrugresistant tuberculosis. We found that isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were N-acetyltransferase 2 and CYP2B6 genotypes, which resulted in a 5-fold difference for both drugs between rapid and slow metabolisers. Bedaquiline exposures were lower during both postpartum and antepartum compared to historical data in non-pregnant patients. For high dose isoniazid, we observed markedly lower isoniazid exposures in participants on combination MDR-TB treatment compared to monotherapy and identified saturable kinetics at doses >10 mg/kg. We suggest that dosing isoniazid based on N-acetyltransferase 2 acetylator status might help patients attain effective exposures against inhA-mutated isolates

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

Gausi, K., Wiesner, L., Norman, J., Wallis, C.L., Onyango-Makumbi, C., Chipato, T., Haas, D.W., Browning, R., Chakhtoura, N., Montepiedra, G., Aaron, L., McCarthy, K., Bradford, S., Vhembo, T., Stranix-Chibanda, L., Masheto, G.R., Violari, A., Mmbaga, B.T., Aurpibul, L., Bhosale, R., Nevrekhar, N., Rouzier, V., Kabugho, E., Mutambanengwe, M., Chanaiwa, V., Nyati, M., Mhembere, T., Tongprasert, F., Hesseling, A., Shin, K., Zimmer, B., Costello, D., Jean-Philippe, P., Sterling, T.R., Theron, G., Weinberg, A., Gupta, A., Denti, P. and (2021), Pharmacokinetics and Drug-Drug Interactions of Isoniazid and Efavirenz in Pregnant Women Living With HIV in High TB Incidence Settings: Importance of Genotyping. Clin. Pharmacol. Ther., 109: 1034-1044. https://doi.org/10.1002/cpt.2044The 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. Eight hundred forty-seven women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6genotypes, which resulted in a five-fold difference for both drugs between rapid and slow metabolizers

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

AimsWe 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.MethodsWe 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. We obtained serial breast milk samples from breastfeeding mothers, and a single plasma sample taken from breastfed and nonbreastfed infants to assess bedaquiline exposure. We used liquid chromatography-tandem mass spectrometry to perform the breast milk and plasma bedaquiline assays, and population PK modelling to interpret the bedaquiline concentrations.ResultsWe recruited 13 women, 6 of whom completed the ante- and postpartum PK sampling. All participants were HIV-positive on antiretroviral therapy. We observed lower ante- and postpartum bedaquiline exposures than reported in nonpregnant controls. Bedaquiline concentrations in breast milk were higher than maternal plasma (milk to maternal plasma ratio: 14:1). A single random plasma bedaquiline and M2 concentration was available in 4 infants (median age: 6.5 wk): concentrations in the 1 breastfed infant were similar to maternal plasma concentrations; concentrations in the 3 nonbreastfed infants were detectable but lower than maternal plasma concentrations.ConclusionWe report low exposure of bedaquiline in pregnant women treated for rifampicin-resistant TB. Bedaquiline significantly accumulates in breast milk; breastfed infants receive mg/kg doses of bedaquiline equivalent to maternal doses

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

BackgroundCritical 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.MethodsDERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with human immunodeficiency virus (HIV) on atazanavir/ritonavir-based antiretroviral therapy (ART) in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg twice a day (BID) with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Dolutegravir 50 mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data were interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L.ResultsWe enrolled 26 participants (23 female) with median (range) age 44 (28-61) years and weight 67 (50-75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, whereas 65% of PK2 Ctau were below the limit of quantification (0.03 mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported a serious adverse event (SAE) or experienced rebound viraemia.ConclusionsTwice daily atazanavir/ritonavir during rifampicin co-administration was well tolerated and achieved plasma concentrations above the target.Clinical trials registrationNCT04121195. Registered on 09 October 2019, https://clinicaltrials.gov/ct2/show/NCT04121195

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

CITATION: Weinberg, A. et al. 2021. Effects of Pregnancy and Isoniazid Preventive Therapy on Mycobacterium tuberculosis Interferon Gamma Response Assays in Women With HIV. Clinical infectious diseases, 73(9): e3555–e3562. doi:10.1093/cid/ciaa1083The original publication is available at https://academic.oup.com/cid/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. Methods 944 women with human immunodeficiency virus infection (HIV) participating in a randomized, double-blind, placebo-controlled study comparing 28 weeks of IPT antepartum versus postpartum, were tested by QuantiFERON-gold-in-tube (QGIT) antepartum and by QGIT and tuberculin skin test (TST) at delivery and postpartum. Serial QGIT positivity was assessed by logistic regression using generalized estimating equations. Results From entry to delivery, 68 (24%) of 284 QGIT-positive women reverted to QGIT-negative or indeterminate. Of these, 42 (62%) recovered QGIT positivity postpartum. The loss of QGIT positivity during pregnancy was explained by decreased interferon gamma (IFNγ) production in response to TB antigen and/or mitogen. At delivery, LTBI was identified by QGIT in 205 women and by TST in 113 women. Corresponding numbers postpartum were 229 and 122 women. QGIT and TST kappa agreement coefficients were 0.4 and 0.5, respectively. Among QGIT-positive women antepartum or at delivery, 34 (12%) reverted to QGIT-negative after IPT. There were no differences between women who initiated IPT antepartum or postpartum. Conclusions Decreased IFNγ responses in pregnancy reduced QGIT positivity, suggesting that this test cannot reliably rule out LTBI during pregnancy. TST was less affected by pregnancy, but had lower positivity compared to QGIT at all time points. IPT was associated with loss of QGIT positivity, the potential clinical consequences of which need to be investigated.https://academic.oup.com/cid/article/73/9/e3555/5877271?login=truePublishers versio

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

AimAlthough 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.MethodsStudy 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.ResultsSodium, potassium, calcium, and chloride levels of all 4 study groups were similar to those of healthy controls. Both HIV-infected groups (UM and SM) had lower red blood cell counts and lower hemoglobin concentration than the reference range. Platelet counts were lower in both HIV-uninfected SM cases (64×109/L) and in the HIV-infected SM cases (66×109/L) compared to the reference range (115-290×109/L). HIV- UM cases had higher proportion and absolute counts of neutrophils and white blood cell counts compared to the HIV+ UM cases.ConclusionHIV infection did not affect the electrolyte profile of Malawian adults presenting with UM or SM but had an effect on red blood cells, Hb concentration, neutrophils, and platelet counts

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 UGT1A1, a gene that codes for uridine diphosphate glucuronosyltransferase. We used population pharmacokinetic modeling to compare the pharmacokinetics of dolutegravir when coadministered with standard- versus high-dose rifampicin in adults with tuberculosis and HIV, and investigated the effect of genetic polymorphisms. Data from the SAEFRIF trial, where participants were randomized to receive first-line tuberculosis treatment with either standard- 10 mg/kg or high-dose 35 mg/kg rifampicin alongside antiretroviral therapy, were used. The dolutegravir model was developed with 211 plasma concentrations from 44 participants. The median (interquartile range) rifampicin area under the curve (AUC) in the standard- and high-dose arms were 32.3 (28.7–36.7) and 153 (138−175) mg·h/L, respectively. A one-compartment model with first-order elimination and absorption through transit compartments best described dolutegravir pharmacokinetics. For a typical 56 kg participant, we estimated a clearance, absorption rate constant, and volume of distribution of 1.87 L/h, 1.42 h−1, and 12.4 L, respectively. Each 10 mg·h/L increase in the AUC of coadministered rifampicin from 32.3 mg·h/L led to a 2.3 (3.1–1.4) % decrease in dolutegravir bioavailability. Genetic polymorphism of UGT1A1 did not significantly affect dolutegravir pharmacokinetics. Simulations of trough dolutegravir concentrations show that the 50 mg twice-daily regimen attains both the primary and secondary therapeutic targets of 0.064 and 0.3 mg/L, respectively, regardless of the dose of coadministered rifampicin, unlike the once-daily regimen

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. This was lower than what previous reports of dose-exposure nonlinearity would predict and was ascribed to 38% lower bioavailability of the rifampicin-only top-up formulation compared to the fixed-dose combination

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. This was lower than what previous reports of dose-exposure nonlinearity would predict and was ascribed to 38% lower bioavailability of the rifampicin-only top-up formulation compared to the fixed-dose combination