HIV genotypic resistance among pregnant women initiating ART in Uganda: a baseline evaluation of participants in the Option B+ clinical trial

Background: Pre-treatment HIV drug resistance is a threat to elimination of mother to child HIV transmission and could lead to virological failure among HIV-positive pregnant women. We analysed genotypic HIV drug resistance (HIVDR) of baseline samples of participants enrolled in the Option B+ clinical trial in Uganda.Methods: HIV-infected pregnant women attending antenatal care were enrolled from Uganda’s National Referral Hospital (Mulago) and Mityana District general hospital and surrounding health centers (HCs). Genotypic HIV testing was performed on blood samples from the first 135 enrolled women out of a subset of 136 participants (25%) who had a baseline VL>1000 copies/mL as one sample failed to amplify.Results: 159/540 (29.4%) had a VL < 1000 copies/ml and 381/540 (70.6%) had a VL >1,000 copies/ml. Of the women with VL>1000 copies/ml, 32 (23.7%) had resistance mutations including 29/135 (21.5%) NNRTI mutations, 6/135 (4.4%) NRTI mutations and 3/135 (2.2%) had both NNRTI and NRTI mutations. The most common NNRTI resistance mutations were: K103KN (5), K103N (5), V179T (4) and E138A (4).Conclusions: One quarter of the HIV-infected pregnant women in this trial at baseline had NNRTI genotypic resistance mutations. Our findings support new WHO guidelines for first-line ART that were changed to dolutegravir-based regimens

'When I receive ARVs through my group, my heart settles': Participants' perceptions and experiences of Friends for Life Circles for Option B+ in Kampala and Mityana Districts, Uganda.

The Friends for Life Circles (FLC) was a parallel randomized controlled trial testing the efficacy of a group peer support intervention to support long-term adherence to Option B+ in Kampala and Mityana districts in Uganda. We explored FLC participants' experiences and perceptions of the intervention on adherence to Option B+ for PMTCT and potential implications for strengthening the PMTCT program. We collected data from six focus group discussions with lactating women enrolled in the FLC intervention, and from 14 key informant interviews with health workers, district and national level stakeholders, as well as male partners of FLC participants. Data were analysed using a content thematic approach in a continuous and iterative process. Women described the FLC intervention as acceptable and beneficial in enhancing their understanding of HIV and the need for ART. The FLC helped women, especially those newly diagnosed with HIV infection to come to terms with their diagnosis and overcome the fear of death linked to testing HIV positive, and provided opportunities to enhance ART initiation, resumption and adherence. The FLC provided safe spaces for women, to learn about ART, and to receive support from peers including adherence reminders through home visits and 'coded' reminder messages. Receiving ART from support groups protected members from stigma and long lines at health facilities. Fear of stigma, health system challenges, the high cost of caring for animals and lack of money to save in groups were key challenges noted. The FLC support groups were crucial in providing needed support for women to initiate, resume and adhere to lifelong ART for Option B+. It is important that women who test HIV positive and start ART for life receive psychosocial support from peers and health workers to improve chances of preventing HIV transmission from mothers to children

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Comment letters to the National Commission on Commission on Fraudulent Financial Reporting, 1987 (Treadway Commission) Vol. 2

https://egrove.olemiss.edu/aicpa_sop/1662/thumbnail.jp

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir