The role of community engagement in promoting research participants' understanding of pharmacogenomic research results: Perspectives of stakeholders involved in HIV/AIDS research and treatment.

Community engagement (CE) is praised to be a powerful vehicle in empowering communities with knowledge and skills to make informed decisions for better health care. Several CE approaches have been proposed to improve participants' and research communities' understanding of genomic research including pharmacogenomic information and results. However, there is limited literature on how these approaches can be used to communicate findings of pharmacogenomic research to communities of people living with HIV. This study explored stakeholders' perspectives on the role of community engagement in promoting understanding of pharmacogenomic research results among people living with HIV. We adopted a qualitative approach that involved 54 stakeholders between September 2021 and February 2022. We held five focus group discussions among 30 community representatives from five research institutions, 12 key informant interviews among researchers, and 12 in-depth interviews among ethics committee members. A thematic approach was used to analyze the results. Five themes merged from this data and these included (i) benefits of engaging communities prior to returning individual pharmacogenomic research results to participants. (ii) Obtaining community consensus on the kinds of pharmacogenomic results to be returned. (iii) Opinions on how pharmacogenomic research information and results should be communicated at community and individual levels. (iv) Perceived roles of community stakeholders in promoting participants' understanding and utilization of pharmacogenomic research results. (v) Perceived challenges of engaging communities when returning individual results to research participants. Stakeholders opined that CE facilitates co-learning between researchers and research communities. Researchers can adapt existing CE approaches that are culturally acceptable for meaningful engagement with minimal ethical and social risks when communicating pharmacogenomic research results. CE approaches can facilitate understanding of pharmacogenomic research and findings among research participants and communities. Therefore, if creatively adapted, existing and new CE approaches can enable researchers to communicate simple and understandable results of pharmacogenomic research.

Support, not blame: safe partner disclosure among women diagnosed with HIV late in pregnancy in South Africa and Uganda.

BACKGROUND: HIV partner disclosure rates remain low among pregnant women living with HIV in many African countries despite potential benefits for women and their families. Partner disclosure can trigger negative responses like blame, violence, and separation. Women diagnosed with HIV late in pregnancy have limited time to prepare for partner disclosure. We sought to understand challenges around partner disclosure and non-disclosure faced by women diagnosed with HIV late in pregnancy in South Africa and Uganda and to explore pathways to safe partner disclosure. METHODS: We conducted in-depth interviews and focus group discussions with pregnant women and lactating mothers living with HIV (n = 109), disaggregated by antenatal care (ANC) initiation before and after 20 weeks of gestation, male partners (n = 87), and health workers (n = 53). All participants were recruited from DolPHIN2 trial sites in Kampala (Uganda) and Gugulethu (South Africa). Topic guides explored barriers to partner disclosure, effects of non-disclosure, strategies for safe disclosure. Using the framework analysis approach, we coded and summarised data based on a socio-ecological model, topic guides, and emerging issues from the data. Data was analysed in NVivo software. RESULTS: Our findings illustrate pregnant women who initiate ANC late experience many difficulties which are compounded by the late HIV diagnosis. Various individual, interpersonal, community, and health system factors complicate partner disclosure among these women. They postpone or decide against partner disclosure mainly for own and baby's safety. Women experience stress and poor mental health because of non-disclosure while demonstrating agency and resilience. We found many similarities and some differences around preferred approaches to safe partner disclosure among female and male participants across countries. Women and male partners preferred healthcare workers to assist with disclosure by identifying the 'right' time to disclose, mentoring women to enhance their confidence and communication skills, and providing professional mediation for partner disclosure and couple testing. Increasing the number of counsellors and training them on safe partner disclosure was deemed necessary for strengthening local health services to improve safe partner disclosure. CONCLUSION: HIV diagnosis late in pregnancy amplifies existing difficulties among pregnant women. Late ANC initiation is an indicator for the likelihood that a pregnant woman is highly vulnerable and needs safeguarding. Respective health programmes should be prepared to offer women initiating ANC late in pregnancy additional support and referral to complementary programmes to achieve safe partner disclosure and good health.

Physiologically-based pharmacokinetic modelling of long-acting injectable cabotegravir and rilpivirine in pregnancy.

AIMS: Long-acting cabotegravir and rilpivirine have been approved to manage HIV in adults, but data regarding safe use in pregnancy are limited. Physiologically-based pharmacokinetic (PBPK) modelling was used to simulate the approved dosing regimens in pregnancy and explore if Ctrough was maintained above cabotegravir and rilpivirine target concentrations (664 and 50 ng/mL, respectively). METHODS: An adult PBPK model was validated using clinical data of cabotegravir and rilpivirine in nonpregnant adults. This was modified by incorporating pregnancy-induced metabolic and physiological changes. The pregnancy PBPK model was validated with data on oral rilpivirine and raltegravir (UGT1A1 probe substrate) in pregnancy. Twelve weeks' disposition of monthly and bimonthly dosing of long-acting cabotegravir and rilpivirine was simulated at different trimesters and foetal exposure was also estimated. RESULTS: Predicted Ctrough at week 12 for monthly long-acting cabotegravir was above 664 ng/mL throughout pregnancy, but below the target in 0.5% of the pregnant population in the third trimester with bimonthly long-acting cabotegravir. Predicted Ctrough at week 12 for monthly and bimonthly long-acting rilpivirine was below 50 ng/mL in at least 40% and over 90% of the pregnant population, respectively, throughout pregnancy. Predicted medians (range) of cord-to-maternal blood ratios were 1.71 (range, 1.55-1.79) for cabotegravir and 0.88 (0.78-0.93) for rilpivirine between weeks 38 and 40. CONCLUSIONS: Model predictions suggest that monthly long-acting cabotegravir could maintain antiviral efficacy throughout pregnancy, but that bimonthly administration may require careful clinical evaluation. Both monthly and bimonthly long-acting rilpivirine may not adequately maintain antiviral efficacy in pregnancy.

Comparison of dolutegravir- and efavirenz on depression, anxiety and sleep disorders in pregnant and postpartum women living with HIV; a DolPHIN2 substudy.

BACKGROUND: Both dolutegravir and efavirenz are known to be effective in pregnancy and post-partum to prevent vertical transmission of HIV and to maintain maternal health. Both drugs have also been associated with neuropsychiatric symptoms. To what extent these symptoms occur in pregnant and post-partum women, however, is not yet known. METHODS: This was a secondary analysis of the DolPHIN2 study, a multicenter randomized trial among women presenting late in pregnancy with untreated HIV- who received either a dolutegravir- or efavirenz- containing regimen. Longitudinal measures of depression, anxiety and sleep quality were analyzed during pregnancy and up to 48 weeks post-partum. RESULTS: Among 268 women median (IQR) Edinburgh Post Natal depression score (EPDS) scores were 8 (3-11) and highest at enrolment. In the dolutegravir -and efavirenz arm, respectively, 23.7% and 25.6% had an EPDS score above 9, indicating possible or probable depression. Abnormal Hospital Anxiety Depression scores (HADS) (above 11) were seen at least once during follow up in 42 of patients (15.7%), although no differences were seen between treatment arms. No association was found between EPDS, suicidality and HADS scores and the assigned regimen (p = 0.93, 0.97 and 0.18 respectively). Median (IQR) Pittsburgh Sleep Quality index (PSQI) scores for dolutegravir- and efavirenz were 6 (5-7) and 5 (5-6.5) respectively, p = 0.70. CONCLUSIONS: No statistically significant differences were observed between efavirenz- or dolutegravir containing regimens. Rates of depression were high, but decreased over the course of time and confirm the need for psychological support after initial HIV diagnosis in pregnancy.

Public Attitudes Towards Access to Health Data for Research Purposes Through Citizens' Jury in Uganda.

Citizens juries (CJ) are a method of deliberative action research that have been utilized in countries with well-funded health care systems to address questions about access to health data. Uganda is classified as a low-income country and utilizes a predominantly paper-based health record system. The burgeoning electronic health record in the central area represents an opportunity to collect and analyze longitudinal data on patients living with long term HIV infection and multiple diseases, a hitherto unexplored disease mapping exercise We set out to understand the public perception towards the use of data for research purposes such as this among Ugandans utilizing an adapted strategy sensitive to the local culture. The jury were unanimous that electronic data should be used for research provided certain safeguards are adhered to and most importantly, that consent to do so is obtained on the basis of a clear rationale for the project.

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 HIV on atazanavir/ritonavir-based 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 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 was interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L. RESULTS: We 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, while 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 an SAE, or experienced rebound viraemia. CONCLUSIONS: Twice daily atazanavir/ritonavir during rifampicin co-administration was well-tolerated and achieved plasma concentrations above the target.

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

Background: 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  Plasmodium falciparum infection, and one in four women have evidence of placental infection at the time of delivery. Artemisinin-based combination therapies (ACTs), primarily artemether-lumefantrine (AL), are the current first-line treatment for uncomplicated Plasmodium falciparum malaria, with the same dosing recommendations in breastfeeding women as those in the adult population. Dihydroartemisinin-piperaquine (DP) is routinely used as an alternative to AL in Uganda. However, lactation pharmacokinetics (PK) of ACTs are unknown. Pharmacokinetic characterization of anti-malarial transfer to breast milk and breastfed infants is crucial in understanding the potential consequences to the infant, in terms of therapeutic- and prophylactic effects as well as potential toxicity.   Methods: This observational study will enroll 30 mother-infant pairs, and aims to characterize the breastmilk transfer of antimalarial medications (AL and DP) to infants when these ACTs are administered to mothers as part of treatment for uncomplicated malaria. In addition, we will assess the mental health of the breastfeeding mothers enrolled as well as the well-being of their children. PK samples of maternal blood, breastmilk and breastfeeding infant's blood will be obtained at specific times points. Pharmacokinetic data will be analyzed using a population pharmacokinetic approach. Conclusions: We anticipate that findings from this research will guide to develop a PK model describing lumefantrine and piperaquine disposition and will provide a framework to foster other lactation pharmacokinetic studies in different disease areas.

Research Participants' Preferences for Individual Results of Pharmacogenomics Research: A Case of a Ugandan HIV Research Institute.

Little is known about whether people living with HIV would like to receive their results from pharmacogenomics research. This study explored the factors influencing participants' preferences and the reasons for their desire to receive individual results from pharmacogenomics research. We employed a convergent parallel mixed methods study design comprising a survey of 225 research participants and 5 deliberative focus group discussions with 30 purposively selected research participants. Almost all (98%) participants wanted to receive individual pharmacogenomics research results. Reasons for the desire to receive results were reciprocity for valuable time and effort, preparing for future eventualities, and the right to information about their health. Overall, participants desire to receive feedback from pharmacogenomics research, particularly if results are well established and clinically actionable.

A systematic review on maternal-to-infant transfer of drugs through breast milk during the treatment of malaria, tuberculosis, and neglected tropical diseases.

BACKGROUND: Exclusive breastfeeding of infants under 6 months of age is recommended by the World Health Organization. In 2021, over 300 million combined incident cases of malaria, tuberculosis, and neglected tropical diseases (NTDs) were reported, predominantly in low-income countries. For many of the drugs used as first-line treatments for these conditions, there is limited knowledge on infant exposure through breastfeeding with poorly understood consequences. This review summarized available knowledge on mother-to-infant transfer of these drugs to inform future lactation pharmacokinetic studies. METHODOLOGY: A list of first-line drugs was generated from the latest WHO treatment guidelines. Using standard online databases, 2 independent reviewers searched for eligible articles reporting lactation pharmacokinetics studies and extracted information on study design, participant characteristics, and the mathematical approach used for parameter estimation. A third reviewer settled any disagreements between the 2 reviewers. All studies were scored against the standardized "ClinPK" checklist for conformity to best practices for reporting clinical pharmacokinetic studies. Simple proportions were used to summarize different study characteristics. FINDINGS: The most remarkable finding was the scarcity of lactation pharmacokinetic data. Only 15 of the 69 drugs we listed had lactation pharmacokinetics fully characterized. Most studies enrolled few mothers, and only one evaluated infant drug concentrations. Up to 66% of the studies used non-compartmental analysis to estimate pharmacokinetic parameters rather than model-based compartmental analysis. Unlike non-compartmental approaches, model-based compartmental analysis provides for dynamic characterization of individual plasma and breast milk concentration-time profiles and adequately characterizes variability within and between individuals, using sparsely sampled data. The "ClinPK" checklist inadequately appraised the studies with variability in the number of relevant criteria across different studies. CONCLUSIONS/SIGNIFICANCE: A consensus is required on best practices for conducting and reporting lactation pharmacokinetic studies, especially in neglected diseases such as malaria, tuberculosis, and NTDs, to optimize treatment of mother-infant pairs.

A "Bundle of Care" to Improve Anticoagulation Control in Patients Receiving Warfarin in Uganda and South Africa: Protocol for an Implementation Study.

BACKGROUND: The quality of warfarin anticoagulation among Sub-Saharan African patients is suboptimal. This is due to several factors, including a lack of standardized dosing algorithms, difficulty in providing timely international normalized ratio (INR) results, a lack of patient feedback on their experiences with treatment, a lack of education on adherence, and inadequate knowledge and training of health care workers. Low quality of warfarin anticoagulation, expressed as time in therapeutic range (TTR), is associated with higher adverse event rates, including bleeding and thrombosis, and ultimately, increased morbidity and mortality. Processes and interventions that improve this situation are urgently needed. OBJECTIVE: This study aims to evaluate the implementation of the "warfarin bundle," a package of interventions to improve the quality of anticoagulation and thereby clinical outcomes. The primary outcome for this study is TTR over the initial 3 months of warfarin therapy. METHODS: Patients aged 18 years or older who are newly initiated on warfarin for venous thromboembolism, atrial fibrillation, or valvular heart disease will be enrolled and followed up for 3 months at clinics in Cape Town, South Africa, and Kampala, Uganda, where the warfarin bundle is implemented. A retrospective review of the clinical records of patients on warfarin treatment before implementation (controls) will be used for comparison. This study uses a mixed methods approach of the implementation of patient- and process-centered activities to improve the quality of anticoagulation. Patient-centered activities include the use of clinical dosing algorithms, adherence support, and root cause analysis, whereas process-centered activities include point-of-care INR testing, staff training, and patient education and training. We will assess the impact of these interventions by comparing the TTR and safety outcomes across the 2 groups, as well as the cost-effectiveness and acceptability of the package. RESULTS: We started recruitment in June 2021 and stopped in August 2022, having recruited 167 participants. We obtained ethics approval from the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, the Provincial Health Research Committees in South Africa, the Joint Clinical Research Centre Institutional Review Board, Kampala, and the University of Liverpool Research Ethics Committee. As of February 2023, data cleaning and formal analysis are underway. We expect to publish the full results by December 2023. CONCLUSIONS: We anticipate that the "bundle of care," which includes a clinical algorithm to guide individualized dosing of warfarin, will improve INR control and TTR of patients in Uganda and South Africa. We will use these findings to design a larger, multisite clinical trial across several Sub-Saharan African countries. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46710.

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. RESULTS: Over the course of one year (July 2017-July 2018), 322 women were screened, with 110 (34.2%) having viral loads of 1000 copies/ml and 62 having whole blood available for genotyping. Fifty-nine of these women had both viral resistance and human host genotypic results. Efavirenz resistance according to metabolizer genotype was; 47% in slow, 34% in extensive and 28% in intermediate metabolizers, but the difference was not statistically significant due to the small sample size. CONCLUSIONS: There was no statistically significant difference in EFV resistance between EFV metabolizer genotypes in women who started antiretroviral therapy during pregnancy and had high viremia in the postpartum period. However, a numerical trend was discovered, which calls for confirmation in a large, well-designed, statistically powered study.

Pharmacovigilance in low- and middle-income countries: A review with particular focus on Africa.

Low- and middle-income countries (LMIC) face unique challenges with regard to the establishment of robust pharmacovigilance systems capable of generating data to inform healthcare policy and practice. These include the limited integration and reliability of pharmacovigilance systems across LMIC despite recent efforts to harmonize pharmacovigilance rules and regulations in several regional economic communities. There are particular challenges relating to the need to translate reporting tools into numerous local languages and the low numbers of healthcare providers relative to number of patients, with very short consultation times. Additional factors frequent in LMIC include high uptake of herbal and traditional medication, mostly by self-medication; disruptive political conflicts jeopardizing fragile systems; and little or no access to drug utilization data, which makes it difficult to reliably estimate the true risks of medicines use. Pharmacovigilance activities are hindered by the scarcity of well-trained personnel with little or no budgetary support from national governments; high turnover of pharmacovigilance staff whose training involves a substantial amount of resources; and little awareness of pharmacovigilance among healthcare workers, decision makers and consumers. Furthermore, little collaboration between public health programmes and national medicines regulatory authorities coupled with limited investment in pharmacovigilance activities, especially during mass drug administration for neglected tropical diseases and mass vaccinations, produces major challenges in establishing a culture where pharmacovigilance is systematically embedded. Very low spontaneous reporting rates with poor quality reports hinders robust signal detection analyses. This review summarises the specific challenges and areas of progress in pharmacovigilance in LMIC with special focus on the situation in Africa.

Communication is crucial: Lessons from COVID-19 vaccination and pregnancy.

The morbidity and mortality from COVID-19 infection are higher in pregnant women compared to their nonpregnant counterparts. As real-world evidence accumulates demonstrating there is no increased risk of adverse maternal and neonatal outcomes associated with COVID-19 vaccination during pregnancy, guidelines have evolved from a case-by-case benefit-risk decision through to clear recommendation in April 2021 for COVID-19 vaccination in pregnancy. However, vaccine hesitancy is a barrier to uptake, especially among the younger population and individuals of ethnic minority backgrounds; pregnant women have additional concerns. Trust in the importance and effectiveness of the vaccine, trust in public health agencies and science, together with good communication methods regarding the safety of COVID-19 vaccines are strong factors for vaccination acceptance in pregnancy. Lack of trust in the health system was worsened by initial knowledge gaps in the information provided about COVID-19 infection and the safety and immunogenicity of COVID-19 vaccines. This was exacerbated by access to incorrect information and misinformation to fill in those knowledge gaps, especially with the increased use of social media. To provide advice and reassurance on COVID-19 vaccine safety to pregnant women, healthcare professionals involved in their care should have the knowledge and skills to provide risk-benefit communication and would benefit from access to training in science communication. Clinical pharmacologists have the expertise to appraise and synthesize emerging pharmacovigilance data, which can inform and support risk-benefit communication by other clinicians. Information should be strategically directed at individual audiences, taking their perspectives and foundational belief systems into consideration.

It Takes A Village; Involvement of Village Health Teams to Develop Tools and Resources to Communicate about Antiretroviral Use in Pregnancy and Breastfeeding at Community Level in Uganda.

Background: Research findings must be communicated to the populations who will benefit from them, in a manner that is accessible and understandable. Aims: We recently generated novel data on medication use in breastfeeding. A Faculty of Health and Life Sciences (Liverpool) grant enabled work with a team of Village Health Teams (VHTs) in Hoima, rural Uganda, to co-create related communication materials for use in their house-to-house visitation and health education. Methods: After an initial workshop from 24th to 26th March 2021, training and review of draft materials, 10 VHT pairs visited 50 households in Hoima district. Basic demographic data were collected alongside preferred communication methods. VHTs provided feedback and re-design of materials commenced. This included dramatization of scenarios and photography. A second round of house-to-house visitation informed final adjustments. We conducted focused group discussions and a dissemination workshop attended by VHTs, local healthcare leaders and journalists was hosted on 16th - 17th June 2022. Results: Most households (74%) had a breastfeeding baby. Majority could read and had access to radios (60%), but not to smartphones (58%) or television (86%). Most preferred verbal and visual aids for health education, and requested images of "people who look like us".Final co-created materials included posters in English and Runyoro and laminated 'job aids' in both languages . These continue to be in active use. VHTs and community members requested future projects of this nature. Conclusion: Healthcare communication to communities must be accessible and clear. Representation of images that the public can identify with is important. Co-creation workshops were successful in rural Uganda, and pave the way for future collaborative, participatory research.

Clinical trials and pregnancy.

Traditionally, there has been a reluctance to involve pregnant people in clinical trials due to complex ethical issues surrounding the risk to unborn babies. However it is crucial that new interventions are safe and effective for all patients and ensuring this can be difficult to achieve in the absence of clinical trials.

A genome-wide association study of plasma concentrations of warfarin enantiomers and metabolites in sub-Saharan black-African patients.

Diversity in pharmacogenomic studies is poor, especially in relation to the inclusion of black African patients. Lack of funding and difficulties in recruitment, together with the requirement for large sample sizes because of the extensive genetic diversity in Africa, are amongst the factors which have hampered pharmacogenomic studies in Africa. Warfarin is widely used in sub-Saharan Africa, but as in other populations, dosing is highly variable due to genetic and non-genetic factors. In order to identify genetic factors determining warfarin response variability, we have conducted a genome-wide association study (GWAS) of plasma concentrations of warfarin enantiomers/metabolites in sub-Saharan black-Africans. This overcomes the issue of non-adherence and may have greater sensitivity at genome-wide level, to identify pharmacokinetic gene variants than focusing on mean weekly dose, the usual end-point used in previous studies. Participants recruited at 12 outpatient sites in Uganda and South Africa on stable warfarin dose were genotyped using the Illumina Infinium H3Africa Consortium Array v2. Imputation was conducted using the 1,000 Genomes Project phase III reference panel. Warfarin/metabolite plasma concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Multivariable linear regression was undertaken, with adjustment made for five non-genetic covariates and ten principal components of genetic ancestry. After quality control procedures, 548 participants and 17,268,054 SNPs were retained. CYP2C9*8, CYP2C9*9, CYP2C9*11, and the CYP2C cluster SNP rs12777823 passed the Bonferroni-adjusted replication significance threshold (p < 3.21E-04) for warfarin/metabolite ratios. In an exploratory GWAS analysis, 373 unique SNPs in 13 genes, including CYP2C9*8, passed the Bonferroni-adjusted genome-wide significance threshold (p < 3.846E-9), with 325 (87%, all located on chromosome 10) SNPs being associated with the S-warfarin/R-warfarin outcome (top SNP rs11188082, CYP2C19 intron variant, p = 1.55E-17). Approximately 69% of these SNPs were in linkage disequilibrium (r 2 > 0.8) with CYP2C9*8 (n = 216) and rs12777823 (n = 8). Using a pharmacokinetic approach, we have shown that variants other than CYP2C9*2 and CYP2C9*3 are more important in sub-Saharan black-Africans, mainly due to the allele frequencies. In exploratory work, we conducted the first warfarin pharmacokinetics-related GWAS in sub-Saharan Africans and identified novel SNPs that will require external replication and functional characterization before they can be considered for inclusion in warfarin dosing algorithms.

Validation and application of a quantitative LC-MS/MS assay for the analysis of first-line anti-tuberculosis drugs, rifabutin and their metabolites in human breast milk.

Breast milk is the preferred method of infant nutrition. Breastfeeding infants born to mothers treated for TB may be at risk of drug toxicity through breast milk exposure, or potentially be vulnerable to select for drug resistance with low level drug exposure. Except for isoniazid, the quantification of first-line TB drugs including rifabutin in breast milk has not been previously described and will provide much-needed insight to TB drug exposure in breastfeeding infants. We developed and validated a novel method to quantify several first-line TB drugs and their major metabolites in breast milk. Accuracy and precision were assessed during three consecutive, independent validation batches over a calibration range of 0.300-30.0 µg/mL for isoniazid and ethambutol, 0.150-15.0 µg/mL for acetyl isoniazid, desacetyl rifampicin, rifampicin, and pyrazinamide, 0.0150-1.50 µg/mL for rifabutin, and 0.00751-0.751 µg/mL for deacetyl rifabutin in breast milk. The method was reproducible for all analytes when using breast milk from six different sources and was not influenced by matrix effects with a mean regression precision (CV(%)) ranging between 1.0 and 2.8. The average recovery of analytes from the matrix was 76.7-99.1%, with a CV(%) between 0.4 and 4.4, while the average process efficiency was between 74.4 and 93.1% with a CV(%) between 1.9 and 8.3. Although only acetyl isoniazid, isoniazid, ethambutol, and pyrazinamide were successfully assayed in breast milk, samples taken from mothers treated for rifampicin-resistant TB and the inclusion of all first-line TB drugs, including rifabutin in the assay development and validation process will allow future quantification of these analytes in breast milk.

72 weeks post-partum follow-up of dolutegravir versus efavirenz initiated in late pregnancy (DolPHIN-2): an open-label, randomised controlled study.

BACKGROUND: Late initiation of antiretrovirals in pregnancy is associated with increased risk of perinatal transmission and higher infant mortality. We report the final 72-week postpartum results for efficacy and safety of dolutegravir-based compared with efavirenz-based regimens in mothers and infants. METHODS: DolPHIN-2 was a randomised, open-label trial. Pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating antiretroviral therapy in third trimester were eligible for inclusion. Eligible women were randomly assigned (1:1) to receive either dolutegravir-based (50 mg dolutegravir, 300 mg tenofovir disoproxil fumarate, and either 200 mg emtricitabine in South Africa or 300 mg lamivudine in Uganda) or efavirenz-based (fixed dose combination 600 mg tenofovir disoproxil fumarate plus either emtricitabine in South Africa or lamivudine in Uganda) therapy. The primary efficacy outcome was the time to a viral load of less than 50 copies per mL measured at 6, 12, 24, 48, and 72 weeks postpartum with a Cox model adjusting for viral load and CD4 cell count. Safety endpoints were summarised by the number of women and infants with events. This trial is registered with ClinicalTrials.gov, NCT03249181. FINDINGS: Between Jan 23 and Aug 15, 2018, 280 women were screened for inclusion, of whom 268 (96%) women were randomly assigned: 133 (50%) to the efavirenz group and 135 (50%) to the dolutegravir group. 250 (93%; 125 [50%] in the efavirenz group and 125 [50%] in the dolutegravir group) women were included in the intention-to-treat analysis of efficacy. Median time to viral load of less than 50 copies per mL was 4·1 weeks (IQR 4·0-5·1) in the dolutegravir group compared with 12·1 weeks (10·7-13·3) in the efavirenz group (adjusted hazard ratio [HR] 1·93 [95% CI 1·5-2·5]). At 72 weeks postpartum, 116 (93%) mothers in the dolutegravir group and 114 (91%) in the efavirenz group had a viral load of less than 50 copies per mL. Of 57 (21%) mothers with a severe adverse event, three (2%) in the dolutegravir group and five (4%) in the efavirenz group were related to the drug (dolutegravir drug-related events were one woman each with suicidal ideation, suicide attempt, herpes zoster meningitis; efavirenz drug-related events were one woman each with suicide attempt and liver cirrhosis, and three people with drug-induced liver injury). Of 136 (56%) infants in whom severe adverse events were recorded, none were related to the study drugs. In addition to the three infant HIV infections detected at birth in the dolutegravir group that have been previously reported, an additional transmission in the efavirenz group occurred during breastfeeding despite optimal maternal viral suppression and serial negative infant tests in the first year of life. INTERPRETATION: Dolutegravir was safe and well tolerated, supporting updated WHO treatment recommendations in pregnant and breastfeeding women. Infant HIV transmissions can occur during breastfeeding despite persistently undetectable maternal viral load highlighting the need for continued infant testing. FUNDING: Unitaid.