Interim analysis, a tool to enhance efficiency of pharmacokinetic studies: Pharmacokinetics of rifampicin in lactating mother-infant pairs.

Pharmacokinetic studies are important for understanding drug disposition in the human body. However, pregnant and lactating women are often excluded from primary pharmacokinetic studies and as such there is often limited dosing information regarding drug use in pregnant and/or lactating women. The objectives of this interim analysis were to define the transfer of rifampicin to a breastfed infant and to determine the area under the concentration-time curve of rifampicin in maternal plasma, breastmilk and infant plasma.

Pharmacokinetics of drugs used to treat drug sensitive-tuberculosis in breastfeeding mother-infant pairs: An observational pharmacokinetic study.

Background: Globally, more than half of women take medicines whilst breastfeeding. Data concerning the exposure of the breastfed infant to drugs and any related risks are sparce. Lactation studies are only rarely performed close to licensing for medicines anticipated to be widely used in women of childbearing age.

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.

-Pharmacokinetics of antimalarial drugs used to treat uncomplicated malaria in breastfeeding mother-infant pairs: An observational pharmacokinetic study.

Data surrounding the exposure of the breastfed infant to drugs and any associated risks are sparse. Drugs usually are transferred to milk in small quantities, and many have been used without obviously noticeable infant toxicity for many years - this lack of a 'safety signal' has further reduced the interest in studying mother-to-infant transfer of the drugs. In sub-Saharan Africa, pregnant women are at risk of   infection, and one in four women have evidence of placental infection at the time of delivery.

Dolutegravir use over 48 weeks is not associated with worsening insulin resistance and pancreatic beta cell function in a cohort of HIV-infected Ugandan adults.

Background: The Uganda Ministry of Health issued restrictive guidelines on the use of dolutegravir (DTG) in persons stratified to have a heightened risk of diabetes mellitus. This followed multiple reports of persons with HIV (PWH) presenting with accelerated hyperglycemia after a few weeks to months of exposure to DTG. Having demonstrated a low incidence of diabetes mellitus and improving blood glucose trajectories in a cohort of ART naïve Ugandan PWH on DTG, we sought to determine whether the observed improvement in blood glucose did not mask background compensated insulin resistance.

Blood glucose outcomes of anti-retroviral therapy naïve Ugandan people with HIV with pre-diabetes mellitus initiated on dolutegravir for 48 weeks.

Background: The Uganda ministry of Health recommends frequent blood glucose monitoring for the first six months on dolutegravir, in people with HIV (PWH) having pre-diabetes mellitus (pre-DM). We sought to determine if indeed PWH with pre-diabetes started on dolutegravir had worse blood glucose outcomes at 48 weeks compared to those with normal blood glucose.

Methods: In this matched cohort study, we compared 44 PWH with pre-DM and 88 PWH with normal blood glucose at baseline.

Pharmacopeial quality of artemether-lumefantrine anti-malarial agents in Uganda.

Background: Substandard anti-malarial agents pose a significant challenge to effective malaria control and elimination efforts especially in sub-Saharan Africa. The quality of anti-malarials in most low-and-middle income countries (LMICs) is affected by several factors including inadequate regulation and limited resources. In this study, the pharmacopeial quality of artemether-lumefantrine (AL) in low and high malaria transmission settings in Uganda was assessed.

Relating CYP2B6 genotype and efavirenz resistance among post-partum women living with HIV with high viremia in Uganda: a nested cross-sectional study.

Background: We investigated the association between CYP2B6 polymorphisms and efavirenz drug resistance among women living with HIV who started on antiretroviral therapy during pregnancy and with high viremia during post-partum.

Methods: This was a cross-sectional study of women with viral loads greater than 1000 copies/ml who were at least 6 weeks postpartum. Sanger sequencing was used to detect resistant mutations, as well as host genotyping, and efavirenz resistance was compared among the metabolizer genotypes.

Building clinical pharmacology laboratory capacity in low- and middle-income countries: Experience from Uganda.

Background: Research and clinical use of clinical pharmacology laboratories are limited in low- and middle-income countries. We describe our experience in building and sustaining laboratory capacity for clinical pharmacology at the Infectious Diseases Institute, Kampala, Uganda.

Intervention: Existing laboratory infrastructure was repurposed, and new equipment was acquired.

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.

Oral pre-exposure prophylaxis preference, uptake, adherence and continuation among adolescent girls and young women in Kampala, Uganda: a prospective cohort study.

Introduction: Oral pre-exposure prophylaxis (PrEP) has been scaled up; however, data from real-world settings are limited. We studied oral PrEP preference, uptake, adherence and continuation among adolescent girls and young women (AGYW) vulnerable to HIV in sub-Saharan Africa.

Methods: We conducted a prospective cohort study among 14- to 24-year-old AGYW without HIV who were followed for 12 months in Kampala, Uganda.

High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults: A Phase II Open-Label Randomized Controlled Trial.

Background: High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity.

Antiretroviral concentration measurements as an additional tool to manage virologic failure in resource limited settings: a case control study.

Background: Several studies demonstrate a correlation between sub-therapeutic concentrations of antiretroviral drugs and virologic failure. We examined the sensitivity, specificity and predictive values of sub-therapeutic drug levels in predicting viralogic failure.

Methods: This was a case control study with cases being samples of participants with virologic failure, and controls samples of participants with virologic suppression.

Low Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?

Antituberculosis drugs display large pharmacokinetic variability, which may be influenced by several factors, including body size, genetic differences, and drug-drug interactions. We set out to determine these factors, quantify their effect, and determine the dose adjustments necessary for optimal drug concentrations. HIV-infected Ugandan adults with pulmonary tuberculosis treated according to international weight-based dosing guidelines underwent pharmacokinetic sampling (1, 2, and 4 h after drug intake) 2, 8, and 24 weeks after treatment initiation.

High efavirenz serum concentrations in TB/HIV-coinfected Ugandan adults with a CYP2B6 516 TT genotype on anti-TB treatment.

Objectives: To report the efavirenz serum concentrations in TB/HIV-coinfected Ugandan adults on concomitant anti-TB treatment and analyse factors associated with elevated concentrations in this specific population.

Methods: Serum efavirenz concentrations in TB/HIV-coinfected Ugandan adults on efavirenz-based ART (600 mg daily) were measured onsite at 2, 8, 12 and 24 weeks of concomitant anti-TB treatment, including rifampicin. Genetic analysis was done retrospectively through real-time PCR by allelic discrimination (CYP2B6 516G>T, rs3745274).

Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients With Low Isoniazid and Rifampicin Concentrations.

Background: The relationship between concentrations of antituberculosis drugs, sputum culture conversion, and treatment outcome remains unclear. We sought to determine the association between antituberculosis drug concentrations and sputum conversion among patients coinfected with tuberculosis and human immunodeficiency virus (HIV) and receiving first-line antituberculosis drugs.

Methods: We enrolled HIV-infected Ugandans with pulmonary tuberculosis.

Cohort profile of a study on outcomes related to tuberculosis and antiretroviral drug concentrations in Uganda: design, methods and patient characteristics of the SOUTH study.

Purpose: Tuberculosis (TB) is a leading cause of death among people living with HIV in sub-Saharan Africa. Several factors influence the efficacy of TB treatment by leading to suboptimal drug concentrations and subsequently affecting treatment outcome. The aim of this cohort is to determine the association between anti-TB drug concentrations and TB treatment outcomes.

Unintended Pregnancies Observed With Combined Use of the Levonorgestrel Contraceptive Implant and Efavirenz-based Antiretroviral Therapy: A Three-Arm Pharmacokinetic Evaluation Over 48 Weeks.

Background: Levonorgestrel subdermal implants are preferred contraceptives with an expected failure rate of <1% over 5 years. We assessed the effect of efavirenz- or nevirapine-based antiretroviral therapy (ART) coadministration on levonorgestrel pharmacokinetics.

Methods: This nonrandomized, parallel group, pharmacokinetic evaluation was conducted in three groups of human immunodeficiency virus-infected Ugandan women: ART-naive (n = 17), efavirenz-based ART (n = 20), and nevirapine-based ART (n = 20).

Low isoniazid and rifampicin concentrations in TB/HIV co-infected patients in Uganda.

Introduction: There is limited data available on exposure to anti-tuberculosis (TB) drugs in this region. Peloquin has described reference ranges [1] however some studies have demonstrated that patients actually achieve concentrations below these ranges [2]. There is limited data about exposure to anti-TB drugs in the HIV/TB co-infected population in Sub-Saharan Africa.

Therapeutic drug monitoring of nevirapine in saliva in Uganda using high performance liquid chromatography and a low cost thin-layer chromatography technique.

Background: In resource limited settings access to laboratory monitoring of HIV treatment is limited and therapeutic drug monitoring is generally unavailable. This study aimed to evaluate nevirapine concentrations in saliva using low-cost thin-layer chromatography (TLC) and nevirapine concentrations in plasma and saliva using high performance liquid chromatography (HPLC) methods; and to correlate nevirapine plasma concentrations to HIV treatment outcomes in Ugandan patients.

Methods: Paired plasma and stimulated saliva samples were obtained from Ugandan, HIV-infected adults on nevirapine-based ART.