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BACKGROUND: We investigated the impact of Drug-Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs. METHODS: Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure. RESULTS: The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%-13.9%) and iron (4%-6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (-21%; Pâ=â0.0271) and C24 (-53%; Pâ=â0.0028). CONCLUSIONS: The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women.
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Favipiravir is a broad-spectrum antiviral that is metabolised intracellularly into the active form, favipiravir ribofuranosyl-5'-triphosphate (F-RTP). Measurement of the intracellular concentration of F-RTP in mononuclear cells is a crucial step to characterising the pharmacokinetics of F-RTP and to enable more appropriate dose selection for the treatment of COVID-19 and emerging infectious diseases. The described method was validated over the range 24 - 2280 pmol/sample. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and lysed using methanol-water (70:30, v/v) before cellular components were precipitated with acetonitrile and the supernatant further cleaned by weak anion exchange solid phase extraction. The method was found to be both precise and accurate and was successfully utilised to analyse F-RTP concentrations in patient samples collected as part of the AGILE CST-6 clinical trial.
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Amidas , Antivirales , Leucocitos Mononucleares , Pirazinas , Humanos , Amidas/química , Antivirales/farmacocinética , Antivirales/análisis , COVID-19 , Tratamiento Farmacológico de COVID-19 , Leucocitos Mononucleares/metabolismo , Cromatografía Líquida con Espectrometría de Masas , Pirazinas/farmacocinética , Pirazinas/análisis , Reproducibilidad de los Resultados , SARS-CoV-2/efectos de los fármacos , Extracción en Fase Sólida/métodos , Espectrometría de Masas en Tándem/métodosRESUMEN
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.
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Revelación , Infecciones por VIH , Femenino , Humanos , Masculino , Embarazo , Infecciones por VIH/diagnóstico , Infecciones por VIH/psicología , Lactancia , Parejas Sexuales/psicología , Sudáfrica , UgandaRESUMEN
BACKGROUND: Both dolutegravir and efavirenz are known to be effective in pregnancy and postpartum 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 postpartum women, however, is not yet known. METHODS: This was a secondary analysis of the DolPHIN2 study, a multicentre randomized trial among women presenting late in pregnancy with untreated HIV - who received either a dolutegravir-containing or efavirenz-containing regimen. Longitudinal measures of depression, anxiety and sleep quality were analysed during pregnancy and up to 48âweeks postpartum. 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 â=â0.93, 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 â=â0.70. CONCLUSION: No statistically significant differences were observed between efavirenz-containing 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.
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Alquinos , Fármacos Anti-VIH , Ansiedad , Benzoxazinas , Ciclopropanos , Depresión , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Piridonas , Trastornos del Sueño-Vigilia , Humanos , Femenino , Benzoxazinas/uso terapéutico , Oxazinas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Embarazo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/complicaciones , Infecciones por VIH/psicología , Piperazinas/uso terapéutico , Piridonas/uso terapéutico , Adulto , Fármacos Anti-VIH/uso terapéutico , Trastornos del Sueño-Vigilia/inducido químicamente , Periodo Posparto/psicología , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/psicología , Adulto Joven , Resultado del TratamientoRESUMEN
Background: A rapid and sensitive LC-MS method has been developed and validated for the quantification of nucleoside di/triphosphates using a novel plasma separation card (HemaSep). Materials & methods: Cards were spotted with whole blood and stored at -80°C. Metabolites were extracted using 70:30 MeOH:20% formic acid, followed by weak anion exchange SPE and eluted using a Biobasic-AX column. Quantification was performed using a triple quadrupole mass spectrometer with a calibration range of 1.25-250 pmol/sample. Results: The recovery of metabolites was high (>93%). Precision and accuracy were acceptable and metabolites remained stable on the card after 29 days (stored at ambient temperature). Conclusion: HemaSep dried blood spots are a useful microsampling tool and offer an alternative to liquid plasma as they maintain stability over time.
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Nucleósidos , Inhibidores de la Transcriptasa Inversa , Cromatografía Liquida/métodos , Nucleótidos , Espectrometría de Masas en Tándem/métodos , Pruebas con Sangre Seca/métodos , Reproducibilidad de los ResultadosRESUMEN
Favipiravir (FVP) is a broad-spectrum antiviral that selectively inhibits viral RNA-dependent RNA polymerase, first trialled for the treatment of influenza infection. It has been shown to be effective against a number of RNA virus families including arenaviruses, flaviviruses and enteroviruses. Most recently, FVP has been investigated as a potential therapeutic for severe acute respiratory syndrome coronavirus 2 infection. A liquid chromatography tandem mass spectrometry method for the quantification of FVP in human plasma has been developed and validated for use in clinical trials investigating favipiravir as treatment for coronavirus disease-2019. Samples were extracted by protein precipitation using acetonitrile, using 13C, 15N- Favipiravir as internal standard. Elution was performed on a Synergi Polar-RP 150 × 2.1 mm 4 µm column using a gradient mobile phase programme consisting of 0.2% formic acid in water and 0.2% formic acid in methanol. The assay was validated over the range 500-50,000 ng/mL; this method was found to be precise and accurate and recovery of FVP from the matrix was high. Stability experiments confirmed and expanded on the known stability of FVP, including under heat treatment and for a period of 10 months at - 80 °C.
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COVID-19 , Espectrometría de Masas en Tándem , Humanos , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Reproducibilidad de los Resultados , Cromatografía Líquida de Alta Presión/métodosRESUMEN
BACKGROUND: The antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19. METHODS: This randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing. FINDINGS: Between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8-9]) than participants in the placebo group (11 days [10-11]; HR 1·30, 95% credible interval 0·92-1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial. INTERPRETATION: We found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive. FUNDING: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust.
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Vacunas contra la COVID-19 , COVID-19 , Adolescente , Adulto , Femenino , Humanos , Masculino , Antivirales , Teorema de Bayes , COVID-19/prevención & control , Vacunas contra la COVID-19/administración & dosificación , Método Doble Ciego , SARS-CoV-2 , Resultado del Tratamiento , Reino UnidoRESUMEN
INTRODUCTION: The extent of vascular/venous access device (VAD) research output from the Island of Ireland is unknown. The identification of the papers available is important to create a future research agenda. OBJECTIVES: The main objective of this study is to answer three questions: What is the number and descriptive quality of reported Vascular Access Device literature from the Island of Ireland? Is the reporting of Catheter Related Infection rates for cancer patients common in Irish Hospital Groups, National Cancer Reports and Publication Outputs? What are the implications for future research in this area? METHODS: We used a scoping review and searched selected databases, grey literature and hospital regulatory bodies websites following the Joanna Briggs Institute Guidelines 2017. A data charting form was developed based on a template from the Joanna Briggs Institute and this was used to extract data from the included reports. RESULTS: A total of 660 reports were screened. Sixty-one full text articles were reviewed from which 20 reports were included for data extraction. Of the reports included the following designs were used: nine retrospective study designs, four guidelines, two prospective study designs, two literature reviews and one of the following; survey, case study and cross sectional analysis designs. We did not identify any randomised controlled trials, systematic reviews, meta-analysis, meta-synthesis and scoping reviews. Five studies included catheter related infection rates. Gaps in the research include the collection of data sets and the need to establish a VAD registry; develop core outcomes for VADs; assessment and evaluation of VAD care bundles among cancer patients; and, the inclusion of public and patient involvement in future VAD research. CONCLUSION: The reporting of VAD outcomes in published literature regarding cancer patients receiving treatment in Ireland is inconsistent and varied with no interventional studies addressing vascular access complications in cancer care.
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Infecciones Relacionadas con Catéteres , Neoplasias , Dispositivos de Acceso Vascular , Humanos , Infecciones Relacionadas con Catéteres/diagnóstico , Infecciones Relacionadas con Catéteres/terapia , Estudios Transversales , Hospitales , Neoplasias/diagnóstico , Neoplasias/terapia , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)-2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations.
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Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Humanos , Antivirales/farmacología , Antivirales/uso terapéutico , Genómica , SARS-CoV-2/genéticaRESUMEN
BACKGROUND: Many women in sub-Saharan Africa initiate antenatal care (ANC) late in pregnancy, undermining optimal prevention of mother-to-child-transmission (PMTCT) of HIV. Questions remain about whether and how late initiation of ANC in pregnancy is related to adherence to antiretroviral therapy (ART) in the era of national dolutegravir roll-out. METHODS: This study employed a qualitative design involving individual interviews and focus group discussions conducted between August 2018 and March 2019. We interviewed 37 pregnant and lactating women living with HIV selected purposively for early or late presentation to ANC from poor urban communities in South Africa and Uganda. Additionally, we carried out seven focused group discussions involving 67 participants in both countries. Data were analysed thematically in NVivo12. RESULTS: Women described common underlying factors influencing both late ANC initiation and poor ART adherence in South Africa and Uganda. These included poverty and time constraints; inadequate health knowledge; perceived low health risk; stigma of HIV in pregnancy; lack of disclosure; and negative provider attitudes. Most late ANC presenters reported relationship problems, lack of autonomy and the limited ability to dialogue with their partners to influence household decisions on health and resource allocation. Perception of poor privacy and confidentiality in maternity clinics was rife among women in both study settings and compounded risks associated with early disclosure of pregnancy and HIV. Women who initiated ANC late and were then diagnosed with HIV appeared to be more susceptible to poor ART adherence. They were often reprimanded by health workers for presenting late which hampered their participation in treatment counselling and festered provider mistrust and subsequent disengagement in care. Positive HIV diagnosis in late pregnancy complicated women's ability to disclose their status to significant others which deprived them of essential social support for treatment adherence. Further, it appeared to adversely affect women's mental health and treatment knowledge and self-efficacy. CONCLUSIONS: We found clear links between late initiation of ANC and the potential for poor adherence to ART based on common structural barriers shaping both health seeking behaviours, and the adverse impact of late HIV diagnosis on women's mental health and treatment knowledge and efficacy. Women who present late are a potential target group for better access to antiretrovirals that are easy to take and decrease viral load rapidly, and counselling support with adherence and partner disclosure. A combination of strengthened health literacy, economic empowerment, improved privacy and patient-provider relationships as well as community interventions that tackle inimical cultural practices on pregnancy and unfair gender norms may be required.
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Infecciones por VIH , Complicaciones Infecciosas del Embarazo , Antirretrovirales/uso terapéutico , Miedo , Femenino , Humanos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Lactancia , Embarazo , Mujeres Embarazadas/psicología , Atención Prenatal/psicología , Sudáfrica , UgandaRESUMEN
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 fumarateâplus eitherâemtricitabine 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.
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Fármacos Anti-VIH , Infecciones por VIH , Alquinos , Fármacos Anti-VIH/efectos adversos , Benzoxazinas/efectos adversos , Ciclopropanos , Quimioterapia Combinada , Emtricitabina/efectos adversos , Femenino , Estudios de Seguimiento , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos , Humanos , Transmisión Vertical de Enfermedad Infecciosa , Lamivudine/efectos adversos , Masculino , Oxazinas , Piperazinas , Periodo Posparto , Embarazo , Piridonas , Tenofovir , Carga ViralRESUMEN
BACKGROUND: Dolutegravir (DTG)-based regimens have been recommended by the WHO as the preferred first-line and second-line HIV treatment in all populations. Evidence suggests an association with weight gain, particularly among black women. Our study investigated perceptions of weight gain from DTG-based regimen use on body image and adherence of antiretroviral therapy in women living with HIV (WLHIV) in Uganda. METHODS: Between April and June 2021, we conducted semi-structured interviews involving 25 WLHIV (adolescents, women of reproductive potential and post-menopausal women) and 19 healthcare professionals (clinicians, nurses, ART managers and counsellors) purposively selected from HIV clinics in Kampala. The interviews explored perceptions of body weight and image; experiences and management of weight related side effects associated with DTG; and knowledge and communication of DTG-related risks. Data was analysed thematically in NVivo 12 software. RESULTS: Our findings indicate WLHIV in Uganda commonly disliked thin body size and aspired to gain moderate to high level body weight to improve their body image, social standing and hide their sero-positive status. Both WLHIV and healthcare professionals widely associated weight gain with DTG use, although it was rarely perceived as an adverse event and was unlikely to be reported or to alter medication adherence. Clinical management and pharmacovigilance of DTG-related weight gain were hampered by the limited knowledge of WLHIV of the health risks of being over-weight and obesity; lack of diagnostic equipment and resources; and limited clinical guidance for managing weight gain and associated cardiovascular and metabolic comorbidities. CONCLUSIONS: The study highlights the significance of large body-size in promoting psychosocial wellbeing in WLHIV in Uganda. Although weight gain is recognized as a side effect of DTG, it may be welcomed by some WLHIV. Healthcare professionals should actively talk about and monitor for weight gain and occurrence of associated comorbidities to facilitate timely interventions. Improved supply of diagnostic equipment and support with sufficient guidance for managing weight gain for healthcare professionals in Uganda are recommended.
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Infecciones por VIH , Adolescente , Peso Corporal , Femenino , Infecciones por VIH/psicología , Compuestos Heterocíclicos con 3 Anillos , Humanos , Oxazinas , Piperazinas , Piridonas , Uganda , Aumento de PesoRESUMEN
INTRODUCTION: Evidence on health-related quality of life (HRQoL) outcomes is limited for new antiretroviral therapies (ART). Dolutegravir-based treatment is being rolled out as the preferred first-line treatment for HIV in many low- and middle-income countries. We compared HRQoL between treatment-naïve pregnant women randomized to dolutegravir- or efavirenz-based ART in a clinical trial in Uganda and South Africa. METHODS: We gathered HRQoL data from 203 pregnant women of mean age 28 years, randomized to either dolutegravir- or efavirenz-based ART. We used the medical outcomes study-HIV health survey at baseline, 24 and 48 weeks between years 2018 and 2019. Physical health summary (PHS) and mental health summary (MHS) scores were the primary study outcomes, while the 11 MOS-HIV subscales were secondary outcomes. We applied mixed model analysis to estimate differences within and between-treatment groups. Multivariate regression analysis was included to identify associations between primary outcomes and selected variables. RESULTS: At 24 weeks postpartum, HRQoL scores increased from baseline in both treatment arms: PHS (10.40, 95% CI 9.24, 11.55) and MHS (9.23, 95% CI 7.35, 11.10) for dolutegravir-based ART; PHS (10.24, 95% CI 9.10, 11.38) and MHS (7.54, 95% CI 5.66, 9.42) for efavirenz-based ART. Increased scores for all secondary outcomes were significant at p < 0.0001. At 48 weeks, improvements remained significant for primary outcomes within group comparison. Estimated difference in PHS were higher in the dolutegravir-based arm, while increases in MHS were more for women in the efavirenz-based armat 24 and 48 weeks. No significant differences were noted for corresponding PHS scores at these time points compared between groups. Differences between arms were observed in two secondary outcomes: role function (1.11, 95% CI 0.08, 2.13), p = 0.034 and physical function outcomes (2.97, 95% CI 1.20, 4.73), p = 0.001. In the multivariate analysis, internet access was associated with higher PHS scores while owning a bank account, using the internet and longer treatment duration were associated with an increase in MHS scores. CONCLUSION: We found no important differences in HRQoL outcomes among HIV-positive women started on dolutegravir relative to efavirenz in late pregnancy. Increases in HRQoL in the first year after delivery provide additional support for the initiation of ART in HIV-positive women presenting late in pregnancy. Trial Registration Clinical Trial Number: NCT03249181.
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Infecciones por VIH , Calidad de Vida , Adulto , Alquinos , Antirretrovirales/uso terapéutico , Benzoxazinas/uso terapéutico , Ciclopropanos , Femenino , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Oxazinas , Piperazinas , Embarazo , Tercer Trimestre del Embarazo , PiridonasRESUMEN
ß-d-N4-hydroxycytidine (NHC), the parent nucleoside of molnupiravir, a COVID-19 antiviral, was quantified at SARS-CoV-2 transmission sites in 12 patients enrolled in AGILE Candidate-Specific Trial-2. Saliva, nasal, and tear NHC concentrations were 3%, 21%, and 22% that of plasma. Saliva and nasal NHC were significantly correlated with plasma (Pâ <â .0001). Clinical Trials Registration. NCT04746183.
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Tratamiento Farmacológico de COVID-19 , Profármacos , Antivirales/uso terapéutico , Citidina/análogos & derivados , Humanos , Hidroxilaminas , Nucleósidos , Padres , Profármacos/uso terapéutico , SARS-CoV-2RESUMEN
Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.
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Antivirales/administración & dosificación , Nitrocompuestos/administración & dosificación , Nitrocompuestos/efectos adversos , Nitrocompuestos/farmacocinética , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Tiazoles/farmacocinética , Adulto , Antivirales/efectos adversos , Antivirales/farmacocinética , Reposicionamiento de Medicamentos , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Tratamiento Farmacológico de COVID-19RESUMEN
OBJECTIVES: AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. METHODS: We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. RESULTS: Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. CONCLUSIONS: Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.
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COVID-19 , SARS-CoV-2 , Adulto , Teorema de Bayes , Humanos , Proyectos de Investigación , Resultado del TratamientoRESUMEN
BACKGROUND: There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. METHODS/DESIGN: AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. DISCUSSION: Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. TRIAL REGISTRATION: EudraCT Number: 2020-001860-27 14 March 2020 ClinicalTrials.gov Identifier: NCT04746183 19 February 2021 ISRCTN reference: 27106947.
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COVID-19 , Pandemias , Estudios de Cohortes , Humanos , SARS-CoV-2 , Resultado del TratamientoRESUMEN
BACKGROUND: Rapid reduction in human immunodeficiency virus (HIV) load is paramount to prevent peripartum transmission in women diagnosed late in pregnancy. We investigated dolutegravir population pharmacokinetics in maternal plasma, umbilical cord, breast milk, and infant plasma samples from DolPHIN-1 participants (NCT02245022) presenting with untreated HIV late in pregnancy (28-36 weeks gestation). METHODS: Pregnant women from Uganda and South Africa were randomized (1:1) to daily dolutegravir (50 mg/d) or efavirenz-based therapy. Dolutegravir pharmacokinetic sampling (0-24 hours) was undertaken 14 days after treatment initiation and within 1-3 weeks after delivery, with matched maternal and cord samples at delivery. Mothers were switched to efavirenz, and maternal and infant plasma and breast milk samples were obtained 24, 48, or 72 hours after the switch. Nonlinear mixed-effects modeling was used to describe dolutegravir in all matrices and to evaluate covariates. RESULTS: A total of 28 women and 22 infants were included. Maternal dolutegravir was described by a 2-compartment model linked to a fetal and breast milk compartment. Cord and breast milk to maternal plasma ratios were 1.279 (1.209-1.281) and 0.033 (0.021-0.050), respectively. Infant dolutegravir was described by breast milk-to-infant and infant elimination rate constants. No covariate effects were observed. The median predicted infant dolutegravir half-life and median time to protein-adjusted 90% inhibitory concentration (0.064 mg/L) for those above this threshold were 37.9 (range, 22.1-63.5) hours and 108.9 (18.6-129.6) hours (4.5 [0.8-5.4] days) (n = 13), respectively. CONCLUSIONS: Breastfeeding contributed relatively little to infant plasma exposure, but a median of 4.5 days of additional prophylaxis to some of the breastfed infants was observed after cessation of maternal dolutegravir (3-15 days postpartum), which waned with time postpartum as transplacental dolutegravir cleared.
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Infecciones por VIH , Leche Humana , Lactancia Materna , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Compuestos Heterocíclicos con 3 Anillos , Humanos , Lactante , Oxazinas , Piperazinas , Placenta , Embarazo , PiridonasRESUMEN
BACKGROUND: Despite concerns about dolutegravir use in pregnancy, most low- and middle-income countries are accelerating the introduction of dolutegravir-based regimens into national antiretroviral treatment programmes. Questions remain about the acceptability of dolutegravir use in women due to the potential risks in pregnancy. This study from South Africa and Uganda explored community values, preferences and attitudes towards the use of dolutegravir-based regimens in women. METHODS: This study employed a qualitative design involving in-depth interviews and focus group discussion conducted between August 2018 to March 2019. The study was conducted in the months following an announcement of a potential risk for neural tube defects with dolutegravir use among women during conception and the first trimester. Participants included HIV positive pregnant and lactating women and their partners. They were selected purposively from urban poor communities in South Africa and Uganda. Data was analysed thematically in NVivo. RESULTS: Forty-four in-depth interviews and 15 focus group discussions were conducted. Most participants had positive views of dolutegravir-based regimens and perceived it to be more desirable compared with efavirenz-containing regimens. There was widespread concern about use of dolutegravir during pregnancy and among women of childbearing age due to publicity around the possible association with neural tube defects. Acceptability was gendered, with nearly all male participants preferring their female spouses of childbearing potential not to use dolutegravir, while most women not planning pregnancy wanted access to contraception alongside dolutegravir. Community awareness and knowledge of dolutegravir was low and characterised by negative information. Women were concerned about HIV-related stigma and wanted the privacy features of dolutegravir to be strengthened with modification of the pill appearance and disguised packaging. CONCLUSIONS: Dolutegravir-based regimens were found to be generally acceptable for use in women except during pregnancy. Interest in a dolutegravir-based regimen was linked with its perceived potential to enhance health, privacy and reduce stigma while concerns about neural tube defects were the main potential barrier to dolutegravir uptake in women. In order to optimise the community acceptability and uptake of acceptability-based regimen among women it is critical to strengthen community awareness and understanding of dolutegravir treatment, improve contraception services alongside the introduction of dolutegravir, and engage with male partners.