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Warfarin dose requirements are highly variable due to clinical and genetic factors. While genetic variants influencing warfarin dose have been identified in European and East Asian populations, more work is needed to identify African-specific genetic variants to help optimize warfarin dosing. We performed genome-wide association studies (GWAS) in four African cohorts from Uganda, South Africa, and Zimbabwe, totalling 989 warfarin-treated participants who reached stable dose and had international normalized ratios within therapeutic ranges. We also included two African American cohorts recruited by the International Warfarin Pharmacogenetics Consortium (n=316) and the University of Alabama at Birmingham (n=199). Following the GWAS, we performed standard error-weighted meta-analyses and then conducted stepwise conditional analyses to account for known loci (the CYP2C cluster SNP rs12777823 and CYP2C9 in chromosome 10; VKORC1 in chromosome 16). The genome-wide significance threshold was set at P<5×10-8. The meta-analysis, comprising 1,504 participants identified 242 significant SNPs across three genomic loci, with 99.6% of these located within known loci on chromosomes 10 (top SNP: rs58800757, P=4.27×10-13) and 16 (top SNP: rs9925964, P=9.97×10-16). Adjustment for the VKORC1 SNP -1639G>A revealed an additional locus on chromosome 2 (top SNPs rs116057875/rs115254730/rs115240773, P=3.64×10-8), implicating the MALL gene, that could indirectly influence warfarin response through interactions with caveolin-1. In conclusion, our meta-analysis of six cohorts of warfarin-treated patients of African ancestry reaffirmed the importance of CYP2C9 and VKORC1 in influencing warfarin dose requirements. We also identified a new locus (MALL), that still requires direct evidence of biological plausibility.
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There is an increasing global burden of diabetes mellitus (DM) and chronic kidney disease (CKD), coupled with a high burden of people with HIV (PWH). Due to an increased lifespan on ART, PWH are now at risk of developing non-communicable diseases, including DM. Africa has the greatest burden of HIV infection and will experience the greatest increase in prevalence of DM over the next two decades. In addition, there is a rising number of people with CKD and progression to kidney failure. Therefore, there is an urgent need for the early identification and management of all 3 diseases to prevent disease progression and complications. This is particularly important in Africa for people with CKD where there is restricted or no access to dialysis and/or transplantation. This review focuses on the epidemiology and pathophysiology of the interaction between HIV infection and DM and the impact that these diseases have on the development and progression of CKD. Finally, it also aims to review the data on the management, which stems from the growing burden of all three diseases.
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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.
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Background: Adolescents are a unique population with significant unmet health needs. They are often excluded from research that may benefit them as they are perceived as vulnerable and needing protection from research participation. For Research Ethics Committees, conflicting positions in statutes, regulations and ethical guidelines about who provides informed consent for adolescent involvement in health research can be a significant barrier to approving adolescent research. For researchers, the requirement for parental/guardian proxy consent or prolonged approval processes may potentially result in the exclusion of those adolescents most vulnerable and at risk, particularly if issues such as gender-based violence, gender identity, sexuality and sexual practices are in question. Objectives: To describe the challenges to adolescent research and suggest strategies to address these. Method: We consider the legal and ethical framework in South Africa regarding the consenting age for adolescents in research, outline the challenges and, using examples of best practices, suggest strategies to address the current conundrum. Results: We suggest three principles to guide Research Ethics Committees on their approach to reviewing health research involving adolescents. Strategies to develop ethically acceptable approaches to adolescent research and consent processes are described, which include community involvement. We elaborate on examples of nuanced approaches to adolescent research. Conclusion: The inclusion of adolescents in research is critical in informing appropriate and effective health services for this vulnerable population, whilst providing an opportunity to link them into care and services where relevant.
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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.
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South Africa has embarked on major health policy reform to deliver universal health coverage through the establishment of National Health Insurance (NHI). The aim is to improve access, remove financial barriers to care, and enhance care quality. Health technology assessment (HTA) is explicitly identified in the proposed NHI legislation and will have a prominent role in informing decisions about adoption and access to health interventions and technologies. The specific arrangements and approach to HTA in support of this legislation are yet to be determined. Although there is currently no formal national HTA institution in South Africa, there are several processes in both the public and private healthcare sectors that use elements of HTA to varying extents to inform access and resource allocation decisions. Institutions performing HTAs or related activities in South Africa include the National and Provincial Departments of Health, National Treasury, National Health Laboratory Service, Council for Medical Schemes, medical scheme administrators, managed care organizations, academic or research institutions, clinical societies and associations, pharmaceutical and devices companies, private consultancies, and private sector hospital groups. Existing fragmented HTA processes should coordinate and conform to a standardized, fit-for-purpose process and structure that can usefully inform priority setting under NHI and for other decision makers. This transformation will require comprehensive and inclusive planning with dedicated funding and regulation, and provision of strong oversight mechanisms and leadership.
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Programas Nacionales de Salud , Evaluación de la Tecnología Biomédica , Seguro de Salud , Sector Privado , Sudáfrica , Cobertura Universal del Seguro de SaludRESUMEN
INTRODUCTION: In December 2019, dolutegravir-based treatment was recommended as first-line antiretroviral therapy (ART) in South Africa. Dolutegravir has clinically significant interactions with several commonly used drugs, such as rifampicin, metformin and cation-containing medicines. National guidelines detail these interactions and how to manage them. While previous international studies have shown low healthcare worker knowledge of drug-drug interactions, there is a paucity of information on antiretroviral interaction knowledge in the South African setting, where much ART is nurse-led. The study aimed to determine this knowledge and to describe which variables were associated with gaps in knowledge. METHODS: An anonymous online survey of healthcare workers in the field of HIV was conducted in August/September 2020. The survey was designed, tested and piloted, and included sections on demographics, guideline access and training, interaction knowledge, counselling and the effect of COVID-19. Dissemination was via e-mail and social media (convenience sampling). Descriptive and inferential analysis was done using proportions and the 95% confidence interval to determine relationships between independent and dependent variables. Research ethics approval was obtained from the University of Cape Town's Human Research Ethics Committee (HREC Ref: 357/2020). RESULTS AND DISCUSSION: In total, 1950 survey responses were included in the analysis - 47.1% nurses, 35.8% doctors and 8.9% pharmacists. When asked whether they were aware that dolutegravir has interactions, 70% said yes, 13.9% said no and 16.1% did not answer. Knowledge of specific interactions and the dosing changes needed was low with a wide range between different drugs: 79.7% knew to double the dolutegravir dose with rifampicin, but with calcium, 5.1% picked both correct dosing options and 33.7% picked one of the two correct options. Access to guidelines and training were positively associated with drug interaction knowledge. CONCLUSIONS: There are gaps in the awareness and knowledge of dolutegravir interactions and how to adjust dosing among South African healthcare workers.
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COVID-19 , Infecciones por VIH , Estudios Transversales , Interacciones Farmacológicas , Infecciones por VIH/tratamiento farmacológico , Conocimientos, Actitudes y Práctica en Salud , Personal de Salud , Compuestos Heterocíclicos con 3 Anillos , Humanos , Oxazinas , Piperazinas , Piridonas , SARS-CoV-2 , SudáfricaRESUMEN
Warfarin remains the most widely prescribed oral anticoagulant in sub-Saharan Africa. However, because of its narrow therapeutic index, dosing can be challenging. We have therefore (a) evaluated and compared the performance of 21 machine-learning techniques in predicting stable warfarin dose in sub-Saharan Black-African patients and (b) externally validated a previously developed Warfarin Anticoagulation in Patients in Sub-Saharan Africa (War-PATH) clinical dose-initiation algorithm. The development cohort included 364 patients recruited from eight outpatient clinics and hospital departments in Uganda and South Africa (June 2018-July 2019). Validation was conducted using an external validation cohort (270 patients recruited from August 2019 to March 2020 in 12 outpatient clinics and hospital departments). Based on the mean absolute error (MAE; mean of absolute differences between the actual and predicted doses), random forest regression (12.07 mg/week; 95% confidence interval [CI], 10.39-13.76) was the best performing machine-learning technique in the external validation cohort, whereas the worst performing technique was model trees (17.59 mg/week; 95% CI, 15.75-19.43). By comparison, the simple, commonly used regression technique (ordinary least squares) performed similarly to more complex supervised machine-learning techniques and achieved an MAE of 13.01 mg/week (95% CI, 11.45-14.58). In summary, we have demonstrated that simpler regression techniques perform similarly to more complex supervised machine-learning techniques. We have also externally validated our previously developed clinical dose-initiation algorithm, which is being prospectively tested for clinical utility.
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Anticoagulantes/administración & dosificación , Aprendizaje Automático , Warfarina/administración & dosificación , Adulto , África del Sur del Sahara , Factores de Edad , Algoritmos , Peso Corporal , Cálculo de Dosificación de Drogas , Femenino , Infecciones por VIH/epidemiología , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Modelos Biológicos , Reproducibilidad de los Resultados , Factores Sexuales , Simvastatina/administración & dosificaciónRESUMEN
Patients in sub-Saharan Africa generally have poor anticoagulation control. We review the potential reasons for this poor control, as well as the potential solutions. Challenges include the affordability and centralisation of anticoagulation care, problems with access to medicines and international normalised ratio monitoring, the lack of locally validated standardized dosing protocols, and low levels of anticoagulation knowledge among healthcare workers and patients. Increasing numbers of patients will need anticoagulation in the future because of the increasing burden of noncommunicable disease in the region. We propose that locally developed "warfarin care bundles" which address multiple anticoagulation challenges in combination may be the most appropriate solution in this setting currently.
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Anticoagulantes , Warfarina , África del Sur del Sahara/epidemiología , Coagulación Sanguínea , Humanos , Relación Normalizada Internacional , Warfarina/efectos adversosRESUMEN
Warfarin has existed for >7 decades and has been the anticoagulant of choice for many thromboembolic disorders. The recent introduction of direct-acting oral anticoagulants (DOACs) has, however, caused a shift in preference by healthcare professionals all over the world. DOACs have been found to be at least as effective as warfarin in prevention of stroke in patients with atrial fibrillation and in treatment of venous thromboembolism. In sub-Saharan Africa, however, the widespread use of DOACs has been hampered mainly by their higher acquisition costs. As the drugs come off patent, their use in sub-Saharan Africa is likely to increase. However, very few trials have been conducted in African settings, and safety concerns will need to be addressed with further study before widespread adoption into clinical practice.
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Fibrilación Atrial , Accidente Cerebrovascular , Administración Oral , África del Sur del Sahara/epidemiología , Anticoagulantes/efectos adversos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Humanos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/prevención & control , Warfarina/efectos adversosRESUMEN
INTRODUCTION: Growing evidence of the teratogenic potential of sodium valproate (VPA) has changed prescribing practices across the globe; however, the impact of this research and the consequent dissemination of a Dear Health Care Professional Letter (DHCPL) in December 2015, recommending avoidance of the teratogen VPA in women of childbearing age (WOCBA) and pregnant women in South Africa, is unknown. We explored trends and reasons for VPA use among pregnant women and WOCBA in the public sector in Western Cape Province from 1 January 2015 to 31 December 2017. METHODS: Using the provincial health information exchange that collates routine electronic health data via unique patient identifiers, we analysed clinical and pharmacy records from 2015 to 2017 to determine prescription patterns of VPA and other antiepileptic drug (AED) and mood-stabilising medicine (MSM) use in WOCBA and pregnant women. Senior clinicians and policy makers were consulted to understand the determinants of VPA use. RESULTS: At least one VPA prescription was dispensed to between 8205 (0.79%) and 9425 (0.94%) WOBCA from a cohort of approximately 1 million WOCBA attending provincial health care facilities per year. Prescriptions were more likely in HIV-infected women compared with HIV-uninfected women (1.1-1.3% vs. 0.7-0.9%; p < 0.001). VPA use in WOCBA remained stable at 0.8-0.9% over the review period despite the 2016 DHCPL. VPA was the most prescribed AED/MSM, constituting 43.2-45.5% of all WOCBA taking at least one such agent, while lamotrigine, the other recommended first-line agent, was only prescribed in 7.8-8.9% of WOCBA. Over 3 years, approximately 663 pregnancies were exposed to VPA, with a steady rise in the number of exposures each year (n = 204, 214 and 245, respectively). CONCLUSION: Despite warnings, VPA remained the most frequently prescribed AED or MSM in WOCBA. Contributing factors are described.
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Epilepsia , Pautas de la Práctica en Medicina , Mujeres Embarazadas , Ácido Valproico , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Embarazo , Sudáfrica , Ácido Valproico/efectos adversos , Ácido Valproico/uso terapéuticoRESUMEN
Warfarin remains the oral anticoagulant of choice in sub-Saharan Africa. However, dosing is challenging due to a highly variable clinical response for a given dose. This study aimed to develop and validate a clinical warfarin dose-initiation model in sub-Saharan Black-African patients. For the development cohort, we used data from 364 patients who were recruited from 8 outpatient clinics and hospital departments in Uganda and South Africa (June 2018-July 2019). Validation was undertaken using the International Warfarin Pharmacogenetics Consortium (IWPC) dataset (690 black patients). Four predictors (age, weight, target International Normalized Ratio range, and HIV status) were included in the final model, which achieved mean absolute errors (MAEs; mean of absolute differences between true dose and dose predicted by the model) of 11.6 (95% confidence interval (CI) 10.4-12.8) and 12.5 (95% CI 11.6-13.4) mg/week in the development and validation cohorts, respectively. Two other clinical models, IWPC and Gage, respectively, obtained MAEs of 12.5 (95% CI 11.3-13.7) and 12.7 (95% CI 11.5-13.8) mg/week in the development cohort, and 12.1 (95% CI 11.2-13.0) and 12.2 (95% CI 11.4-13.1) mg/week in the validation cohort. Compared with fixed dose-initiation, our model decreased the percentage of patients at high risk of suboptimal anticoagulation by 7.5% (1.5-13.7%) and 11.9% (7.1-16.8%) in the development and validation cohorts, respectively. The clinical utility of this model will be tested in a prospective study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? â Warfarin dosing remains challenging due to a highly variable clinical response for a given dose. WHAT QUESTION DID THIS STUDY ADDRESS? â Can a clinical dose-initiation model be developed and validated for sub-Saharan Black-African patients? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? â We have developed the first warfarin dose-initiation clinical model for Black-African patients in Uganda and South Africa. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? â We will be implementing and validating this model in a prospective cohort to inform future large-scale implementation. More optimized dosing should improve the quality of warfarin anticoagulation in these two developing countries.
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Población Negra , Warfarina/administración & dosificación , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Peso Corporal , Niño , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Seropositividad para VIH , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Sudáfrica , Resultado del Tratamiento , Uganda , Warfarina/efectos adversos , Warfarina/uso terapéutico , Adulto JovenRESUMEN
Cannabinoids are a diverse class of chemical compounds that are increasingly recognized as potential therapeutic options for a range of conditions. While many studies and reviews of cannabinoids focus on efficacy, safety is much less well reported. Overall assessment of the safety of cannabinoid-based medicines is confounded by confusion with recreational cannabis use as well as different study designs, indications, dosing, and administration methods. However, clinical studies in registered products are increasingly available, and this article aims to discuss and clarify what is known regarding the safety profiles of cannabinoid-based medicines, focusing on the medical and clinical safety evidence and identifying areas for future research. The two most well-studied cannabinoids are Δ9-tetrahydrocannabinol (THC), or its synthetic variants (dronabinol, nabilone), and cannabidiol (CBD). Across diverse indications, dizziness and fatigue are generally the most common adverse events experienced by patients receiving THC or combined THC and CBD. Patients receiving THC may experience adverse cognitive effects and impairment in psychomotor skills, with implications for driving and some occupations, while CBD may help to lower the psychotropic effects of THC when used in combination. Studies on dependency and addiction in a medical context are limited, but have shown inconsistent findings regarding misuse potential. Generally, the recommended route of administration is oral ingestion, as smoking medicinal cannabinoid products potentially releases mutagenic and carcinogenic by-products. There are several potential drug-drug interactions and contraindications for cannabinoid-based medicines, which physicians should account for when making prescribing decisions. The available evidence shows that, as with any other class of pharmaceuticals, cannabinoid-based medicines are associated with safety risks which should be assessed in the context of potential therapeutic benefits. Each patient should be assessed on an individual basis and physicians must rely on informed, evidence-based decision-making when determining whether a cannabinoid-based medicine could be an appropriate treatment option.
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Human immunodeficiency virus (HIV) affects over 36 million people worldwide. Antiretroviral therapy (ART) is expanding and improving HIV viral suppression, resulting in increasing exposure to drugs and drug interactions. Polypharmacy is a common complication as people are living longer on ART, increasing the risk of drug toxicities. Polypharmacy is related not only to ART exposure and medication for opportunistic infections, but also to treatment of chronic lifestyle diseases. Acute kidney injury (AKI) is frequent in HIV and is commonly the result of sepsis, dehydration and drug toxicities. Furthermore, HIV itself increases the risk of chronic kidney disease (CKD). Drug treatment is often complicated in people living with HIV because of a greater incidence of AKI and/or CKD compared to the HIV-negative population. Impaired renal function affects drug interactions, drug toxicities and importantly drug dosing, requiring dose adjustment. This review discusses ART and its nephrotoxic effects, including drug-drug interactions. It aims to guide the clinician on dose adjustment in the setting of renal impairment and dialysis, for the commonly used drugs in patients with HIV.
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INTRODUCTION: Warfarin is the most commonly prescribed oral anticoagulant in sub-Saharan Africa and requires ongoing monitoring. The burden of both infectious diseases and non-communicable diseases is high and medicines used to treat comorbidities may interact with warfarin. We describe service provision, patient characteristics, and anticoagulation control at selected anticoagulation clinics in Uganda and South Africa. METHODS: We evaluated two outpatient anticoagulation services in Kampala, Uganda and three in Cape Town, South Africa between 1 January and 31 July 2018. We collected information from key staff members about the clinics' service provision and extracted demographic and clinical data from a sample of patients' clinic records. We calculated time in therapeutic range (TTR) over the most recent 3-month period using the Rosendaal interpolation method. RESULTS: We included three tertiary level, one secondary level and one primary level anticoagulation service, seeing between 30 and 800 patients per month. Care was rendered by nurses, medical officers, and specialists. All healthcare facilities had on-site pharmacies; laboratory INR testing was off-site at two. Three clinics used warfarin dose-adjustment protocols; these were not validated for local use. We reviewed 229 patient clinical records. Most common indications for warfarin were venous thrombo-embolism in 112/229 (49%), atrial fibrillation in 74/229 (32%) and valvular heart disease in 30/229 (13%). Patients were generally followed up monthly. HIV prevalence was 20% and 5% at Ugandan and South African clinics respectively. Cardiovascular comorbidity predominated. Furosemide, paracetamol, enalapril, simvastatin, and tramadol were the most common concomitant drugs. Anticoagulation control was poor at all included clinics with median TTR of 41% (interquartile range 14% to 69%). CONCLUSIONS: TTR was suboptimal at all included sites, despite frequent patient follow-up. Strategies to improve INR control in sub-Saharan patients taking warfarin are needed. Locally validated warfarin dosing algorithms in Uganda and South Africa may improve INR control.
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Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Enfermedades de las Válvulas Cardíacas/tratamiento farmacológico , Tromboembolia Venosa/tratamiento farmacológico , Warfarina/uso terapéutico , Adulto , Anciano , Atención Ambulatoria , Fibrilación Atrial/complicaciones , Estudios Transversales , Monitoreo de Drogas , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Infecciones por VIH/patología , Enfermedades de las Válvulas Cardíacas/complicaciones , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Centros de Atención Secundaria , Sudáfrica/epidemiología , Centros de Atención Terciaria , Uganda/epidemiología , Tromboembolia Venosa/complicacionesAsunto(s)
Anticoagulantes/efectos adversos , Fibrilación Atrial/tratamiento farmacológico , Coagulación Sanguínea/efectos de los fármacos , Enfermedades de las Válvulas Cardíacas/tratamiento farmacológico , Hemorragia/inducido químicamente , Embolia Pulmonar/tratamiento farmacológico , Warfarina/efectos adversos , Anticoagulantes/administración & dosificación , Fibrilación Atrial/sangre , Fibrilación Atrial/mortalidad , Monitoreo de Drogas/métodos , Enfermedades de las Válvulas Cardíacas/sangre , Enfermedades de las Válvulas Cardíacas/mortalidad , Humanos , Relación Normalizada Internacional , Embolia Pulmonar/sangre , Embolia Pulmonar/mortalidad , Factores de Riesgo , Resultado del Tratamiento , Warfarina/administración & dosificaciónRESUMEN
BACKGROUND: Gynaecomastia is associated with exposure to antiretroviral therapy (ART), in particular efavirenz. There is limited data on clinical characteristics of patients with ART-associated gynaecomastia in resource-limited settings and little guidance on the optimal management of this adverse drug reaction (ADR). We describe the clinical characteristics, management and outcomes of gynaecomastia cases reported to the National HIV & Tuberculosis Health Care Worker Hotline in South Africa. METHODS: We identified all gynaecomastia cases in adolescent boys and men on ART reported to the hotline between June 2013 and July 2014. We collected follow up data telephonically at monthly intervals to document clinical management and outcomes. RESULTS: We received 51 reports of gynaecomastia between June 2013 and July 2014; 11% of the 475 patient-specific ADR queries to the hotline. All patients were on efavirenz-based ART. Mean age was 34 years (standard deviation 12) and seven were adolescents. The median onset of gynaecomastia was 15 months after efavirenz initiation (interquartile range 6-42). Gynaecomastia was bilateral in 29 patients (57%) and unilateral in 16 (31%). Serum testosterone was quantified in 25 of 35 patients with follow up data, and was low in 2 (8%). Efavirenz was replaced with an alternative antiretroviral in 29/35 patients (83%) and gynaecomastia improved in 20/29 (69%). CONCLUSIONS: Gynaecomastia was a frequently reported ADR in our setting, occurring with prolonged efavirenz exposure. Testosterone was low in the minority of tested cases. Most clinicians elected to switch patients off efavirenz, and gynaecomastia improved in the majority.
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Fármacos Anti-VIH/efectos adversos , Ginecomastia/epidemiología , Líneas Directas/estadística & datos numéricos , Adolescente , Adulto , Alquinos , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Benzoxazinas/efectos adversos , Benzoxazinas/uso terapéutico , Niño , Ciclopropanos , Ginecomastia/inducido químicamente , Ginecomastia/diagnóstico , Ginecomastia/terapia , Infecciones por VIH/tratamiento farmacológico , Personal de Salud , Humanos , Masculino , Persona de Mediana Edad , Sudáfrica/epidemiología , Testosterona/sangre , Resultado del TratamientoRESUMEN
Limited data exist on the burden of serious adverse drug reactions (ADRs) in sub-Saharan Africa, which has high HIV and tuberculosis prevalence. We determined the proportion of adult admissions attributable to ADRs at 4 hospitals in South Africa. We characterized drugs implicated in, risk factors for, and the preventability of ADR-related admissions.We prospectively followed patients admitted to 4 hospitals' medical wards over sequential 30-day periods in 2013 and identified suspected ADRs with the aid of a trigger tool. A multidisciplinary team performed causality, preventability, and severity assessment using published criteria. We categorized an admission as ADR-related if the ADR was the primary reason for admission.There were 1951 admissions involving 1904 patients: median age was 50 years (interquartile range 34-65), 1057 of 1904 (56%) were female, 559 of 1904 (29%) were HIV-infected, and 183 of 1904 (10%) were on antituberculosis therapy (ATT). There were 164 of 1951 (8.4%) ADR-related admissions. After adjustment for age and ATT, ADR-related admission was independently associated (Pâ≤â0.02) with female sex (adjusted odds ratio [aOR] 1.51, 95% confidence interval [95% CI] 1.06-2.14), increasing drug count (aOR 1.14 per additional drug, 95% CI 1.09-1.20), increasing comorbidity score (aOR 1.23 per additional point, 95% CI 1.07-1.41), and use of antiretroviral therapy (ART) if HIV-infected (aOR 1.92 compared with HIV-negative/unknown, 95% CI 1.17-3.14). The most common ADRs were renal impairment, hypoglycemia, liver injury, and hemorrhage. Tenofovir disoproxil fumarate, insulin, rifampicin, and warfarin were most commonly implicated, respectively, in these 4 ADRs. ART, ATT, and/or co-trimoxazole were implicated in 56 of 164 (34%) ADR-related admissions. Seventy-three of 164 (45%) ADRs were assessed as preventable.In our survey, approximately 1 in 12 admissions was because of an ADR. The range of ADRs and implicated drugs reflect South Africa's high HIV and tuberculosis burden. Identification and management of these ADRs should be considered in HIV and tuberculosis care and treatment programs and should be emphasized in health care worker training programmes.
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Fármacos Anti-VIH/efectos adversos , Antituberculosos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Hospitalización/estadística & datos numéricos , Hospitales/estadística & datos numéricos , Adulto , Anciano , Estudios Transversales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Estudios Prospectivos , Factores de Riesgo , Factores Sexuales , Sudáfrica/epidemiología , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/epidemiologíaRESUMEN
INTRODUCTION: The National HIV & Tuberculosis Health Care Worker (HCW) Hotline provides advice on the management of suspected adverse drug reactions (ADRs). We describe suspected ADRs reported to the hotline by HCWs, concordance with advice, and patient outcomes. METHODS: We reviewed suspected ADRs in HIV-infected patients, patients taking antiretrovirals and patients taking anti-tuberculosis therapy reported from May 2013 to October 2014. We performed causality assessment using the World Health Organization Uppsala Monitoring Centre (WHO-UMC) criteria. We included suspected ADRs categorized as certain, probable or possible in further analysis. RESULTS: We received 772 ADR reports, of which 87/772 (11.3%) were classified as certain, 176/772 (22.8%) as probable, 361/772 (46.8%) as possible, and 148/772 (19.2%) as unlikely or unassessable. The most frequent ADRs were rash, drug-induced liver injury (DILI) and kidney injury, comprising 110/624 (17.6%), 87/624 (13.9%), and 77/624 (12.3%), respectively. The ADR was severe in 27.3% of rashes, 36.4% of kidney injury reports and 88.5% of DILI reports. Most frequently implicated drugs, either alone or in combination with other potentially causative drugs, were efavirenz (rashes), efavirenz and anti-tuberculosis drugs (DILI) and tenofovir (kidney injury). In 383 cases with HCW follow-up, 254 (66.3%) improved, 9 (2.3%) had complete resolution, 32 (8.4%) remained unchanged, 6 (1.6%) deteriorated, 10 (2.6%) died and 72 (18.8%) had unknown outcome. Advice provided was followed in 93.2% of these cases. Of 223 ADRs with preventability data, 40 (17.9%) were preventable. CONCLUSION: Queries about rashes, DILIs and kidney injuries were common. Detection and management of these ADRs should be included in HCW training. In cases with follow-up, concordance with advice was high, and HCWs reported improvement in the majority.
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Lesión Renal Aguda/epidemiología , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Fármacos Anti-VIH/efectos adversos , Antituberculosos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Lesión Renal Aguda/etiología , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Antituberculosos/administración & dosificación , Antituberculosos/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Estudios Prospectivos , Tuberculosis/tratamiento farmacológico , Tuberculosis/epidemiologíaRESUMEN
Special populations, including children and pregnant women, have been neglected in tuberculosis drug development. Patients in developing countries are inadequately represented in pharmacology research, and postmarketing pharmacovigilance activities tend to be rudimentary in these settings. There is an ethical imperative to generate evidence at an early stage to support optimal treatment in these populations and in populations with common comorbid conditions, such as diabetes and human immunodeficiency virus (HIV) infection. This article highlights the research needed to support equitable access to new antituberculosis regimens. Efficient and opportunistic pharmacokinetic study designs, typically using sparse sampling and population analysis methods, can facilitate optimal dose selection for children and pregnant women. Formulations suitable for children should be developed early and used in pharmacokinetic studies to guide dose selection. Drug-drug interactions between commonly coprescribed medications also need to be evaluated, and when these are significant, alternative approaches should be sought. A potent rifamycin-sparing regimen could revolutionize the treatment of adults and children requiring a protease inhibitor as part of antiretroviral treatment regimens for HIV infection. A sufficiently wide formulary of drugs should be developed for those with contraindications to the standard approaches. Because genetic variations may influence an individual's response to tuberculosis treatment, depending on the population being treated, it is important that samples be collected and stored for pharmacogenetic study in future clinical trials.