Tackling antimicrobial resistance: developing and implementing antimicrobial stewardship interventions in four African commonwealth countries through a health partnership model.

In recent years, health partnerships have shared infection prevention and control innovations between United Kingdom hospitals and Low-Middle-Income Countries. However, none had focused on antimicrobial stewardship (AMS), a core component of tackling antimicrobial resistance (AMR). This paper documents an effective approach to developing a program to increase AMS capacity in four African countries: Ghana, Tanzania, Uganda, and Zambia as part of the Commonwealth Partnerships for Antimicrobial Stewardship (CwPAMS) program. A systematic approach was applied to assess gaps in AMS interventions and inform the development of the CwPAMS program through deskbased assessments, including National Action Plans on AMR, online focus group meetings, and expert advisory group reviews. Twelve partnerships were selected for the CwPAMS program. AMS support tools were developed based on recommendations from the scoping, including an AMS checklist tool, a healthcare worker knowledge and attitudes questionnaire, and an antimicrobial prescribing app to support clinical decision-making. Training workshops on AMS were developed and delivered to volunteers in Africa and the UK using a train-the-trainer model. The tools and workshops facilitated capacity building for AMS through the generation and strengthening of knowledge, skills, commitment, structures, systems, and leadership among stakeholders in the UK and Africa. The overall average rating assigned to the program following independent evaluation using the Organisation for Economic Cooperation and Development Assistance Committee Evaluation Criteria was very good. The evaluation also highlighted that the majority of the HPs (75%) focused on AMS and/or improved prescribing practice; all HPs have developed and implemented AMS strategies, guidelines, and tools within their hospitals; and NHS staff were able to translate the knowledge and skills they had received early on in the program into clinical practice in response to COVID-19 challenges.

Supply-chain factors and antimicrobial stewardship.

Efficient and secure supply chains are vital for effective health services worldwide. In low- and middle-income countries, the accessibility, affordability and availability of essential medicines, including antimicrobials, remain challenging. Ineffective supply chains often cause antimicrobial shortages, leading to inappropriate use of alternative agents and increasing the risk of antimicrobial resistance. Shortages, coupled with insecure supply chains, also encourage the infiltration of substandard and falsified medicines, leading to suboptimal treatment and further promoting antimicrobial resistance. Addressing antimicrobial supply-chain issues should be considered a key component of antimicrobial stewardship programmes. We have explored the link between medicine supply chains and antimicrobial use in seven focus countries: Kenya, Malawi, Nigeria, Sierra Leone, Uganda, United Republic of Tanzania and Zambia. We explored country medicine supply-system structures, national medicine supply-chain policy documents and global study reports. Our aim was to develop evidence-based strategies to enhance the effectiveness and efficiency of the medicine supply chains in supporting antimicrobial stewardship efforts. Better management of medical supply chains involves rational selection, quantification, forecasting, procurement, storage, distribution, use and stock management of antimicrobials. Important supply-chain considerations include pooled procurement networks to ensure consistent pricing of quality-assured antimicrobials, and improved resource utilization and information exchange among relevant stakeholders. We propose adaptable recommendations for integrating medicine supply chains as an essential part of antimicrobial stewardship programmes, with a call for action at the local, regional and national levels in low- and middle-income countries.

Partout dans le monde, les performances des services de santé dépendent de l'efficacité et de la sécurité des chaînes d'approvisionnement. Mais dans les pays à revenu faible et intermédiaire, l'accessibilité et la disponibilité des médicaments à prix abordable, y compris des antimicrobiens, représentent toujours un défi. L'inefficacité des chaînes d'approvisionnement entraîne souvent des pénuries d'antimicrobiens et, par conséquent, un recours à des alternatives inappropriées et une augmentation du risque de résistance aux antimicrobiens. Ces pénuries, alliées à des chaînes d'approvisionnement peu fiables, favorisent également l'introduction de médicaments falsifiés et de qualité inférieure, altérant l'efficacité du traitement et renforçant encore davantage la résistance aux antimicrobiens. Résoudre les problèmes liés aux chaînes d'approvisionnement en antimicrobiens devrait donc figurer parmi les priorités des programmes de gestion des antimicrobiens. Le présent document s'intéresse au lien entre les chaînes d'approvisionnement en médicaments et l'utilisation d'antimicrobiens dans sept pays cibles: le Kenya, le Malawi, le Nigeria, l'Ouganda, la République-Unie de Tanzanie, la Sierra Leone et la Zambie. Pour chacun de ces pays, nous avons examiné les structures du système d'approvisionnement en médicaments, les documents relatifs à la politique d'approvisionnement national et les rapports d'études globaux. Notre objectif consistait à développer des stratégies fondées sur des données factuelles, afin d'améliorer le fonctionnement et l'efficacité des chaînes d'approvisionnement en médicaments et de contribuer ainsi aux efforts de gestion des antimicrobiens. Une meilleure logistique requiert une certaine rationalité dans la sélection, la quantification, la planification, l'approvisionnement, le stockage, la distribution, l'utilisation et la gestion des stocks d'antimicrobiens. Dans ce contexte, plusieurs éléments sont importants tels que les réseaux d'achats groupés, qui assurent la stabilité des prix pour des antimicrobiens de qualité garantie, ou encore l'optimisation des ressources et l'échange d'informations entre les acteurs concernés. Nous formulons des recommandations ajustables en vue de rendre les chaînes d'approvisionnement en médicaments incontournables dans les programmes de gestion des antimicrobiens, avec un appel à agir à l'échelle locale, régionale et nationale dans les pays à revenu faible et intermédiaire.

Unas cadenas de suministro eficientes y seguras son vitales para la eficacia de los servicios sanitarios en todo el mundo. En los países de ingresos bajos y medios, la accesibilidad, asequibilidad y disponibilidad de los medicamentos esenciales, incluidos los antimicrobianos, sigue siendo un reto. Con frecuencia, las cadenas de suministro ineficaces provocan escasez de antimicrobianos, lo que conlleva un uso inadecuado de agentes alternativos y aumenta el riesgo de resistencia a los antimicrobianos. La escasez, sumada a la inseguridad de las cadenas de suministro, también favorece la infiltración de medicamentos de calidad inferior y adulterados, lo que conduce a un tratamiento subóptimo y fomenta aún más la resistencia a los antimicrobianos. Abordar los problemas de la cadena de suministro de antimicrobianos se debería considerar un componente clave de los programas de administración de antimicrobianos. Hemos explorado la relación entre las cadenas de suministro de medicamentos y el uso de antimicrobianos en siete países seleccionados: Kenia, Malawi, Nigeria, Sierra Leona, Uganda, República Unida de Tanzania y Zambia. Exploramos las estructuras de los sistemas de suministro de medicamentos de los países, los documentos de política nacional sobre la cadena de suministro de medicamentos y los informes de estudios globales. Nuestro objetivo era desarrollar estrategias basadas en evidencias para mejorar la eficacia y la eficiencia de las cadenas de suministro de medicamentos en apoyo de los esfuerzos de administración antimicrobiana. Una mejor gestión de las cadenas de suministro de medicamentos implica la selección racional, la cuantificación, la previsión, la adquisición, el almacenamiento, la distribución, el uso y la gestión de las existencias de antimicrobianos. Entre las consideraciones importantes sobre la cadena de suministro se incluyen las redes de adquisición mancomunada para garantizar precios coherentes de antimicrobianos de calidad garantizada y una mejor utilización de los recursos e intercambio de información entre las partes interesadas pertinentes. Proponemos recomendaciones adaptables para integrar las cadenas de suministro de medicamentos como parte esencial de los programas de administración de antimicrobianos, con una llamada a la acción a nivel local, regional y nacional en los países de ingresos bajos y medios.

Scoping of pharmacists' health leadership training needs for effective antimicrobial stewardship in Africa.

BACKGROUND: Antimicrobial resistance (AMR) is a global public health concern currently mitigated by antimicrobial stewardship (AMS). Pharmacists are strategically placed to lead AMS actions that contribute to responsible use of antimicrobials; however, this is undermined by an acknowledged health leadership skills deficit. Learning from the UK's Chief Pharmaceutical Officer's Global Health (ChPOGH) Fellowship programme, the Commonwealth Pharmacists Association (CPA) is focused to develop a health leadership training program for pharmacists in eight sub-Saharan African countries. This study thus explores need-based leadership training needs for pharmacists to provide effective AMS and inform the CPA's development of a focused leadership training programme, the 'Commonwealth Partnerships in AMS, Health Leadership Programme' (CwPAMS/LP). METHODS: A mixed methods approach was undertaken. Quantitative data were collected via a survey across 8 sub-Saharan African countries and descriptively analysed. Qualitative data were collected through 5 virtual focus group discussions, held between February and July 2021, involving stakeholder pharmacists from different sectors in the 8 countries and were analysed thematically. Data were triangulated to determine priority areas for the training programme. RESULTS: The quantitative phase produced 484 survey responses. Focus groups had 40 participants from the 8 countries. Data analysis revealed a clear need for a health leadership programme, with 61% of respondents finding previous leadership training programmes highly beneficial or beneficial. A proportion of survey participants (37%) and the focus groups highlighted poor access to leadership training opportunities in their countries. Clinical pharmacy (34%) and health leadership (31%) were ranked as the two highest priority areas for further training of pharmacists. Within these priority areas, strategic thinking (65%), clinical knowledge (57%), coaching and mentoring (51%), and project management (58%) were selected as the most important. CONCLUSIONS: The study highlights the training needs of pharmacists and priority focus areas for health leadership to advance AMS within the African context. Context-specific identification of priority areas supports a needs-based approach to programme development, maximising African pharmacists' contribution to AMS for improved and sustainable patient outcomes. This study recommends incorporating conflict management, behaviour change techniques, and advocacy, amongst others, as areas of focus to train pharmacist leaders to contribute to AMS effectively.

Evaluation of HIV viral load turnaround time in Moshi, Tanzania.

INTRODUCTION: Viral load measurement is an important gold standard for monitoring anti-retroviral treatment among people living with human immunodeficiency virus. The optimal use of the viral load results for guiding antiretroviral therapy depends on timely availability of the results at the clinic. The objective of the current study was to evaluate the turnaround time and utilization of viral load results in the clinical decision process. METHODOLOGY: This was a retrospective cohort study which involved patients receiving cART from 1 August 2018 to 31 January 2017 at three clinics in Tanzania. Data was extracted from patient files at the clinics and relevant records were kept at the viral load determining laboratory. The data were analysed with the Statistical Package for Social Sciences version 20. RESULTS: 445 subjects had a viral load in test results and 88% had a viral load of > 1,000 copies/mL. The median duration on the current regimen was five years. Median time between the clinics receiving the results and communicating them to the patients was 40 days. Shorter turnaround time was observed for patients with virological failure (p = 0.003). A higher prevalence of virological failure was found in patients monitored at the Kilimanjaro Christian Medical Centre (KCMC) compared to the two primary health clinics (p = 0.04). CONCLUSIONS: The median viral load turnaround time was longer than stipulated by the national Tanzanian guidelines. Interventions that may reduce viral load turn-around-time, including point of care viral load testing, are needed to optimise monitoring of anti-retroviral therapy.

Scoping Review of National Antimicrobial Stewardship Activities in Eight African Countries and Adaptable Recommendations.

Antimicrobial resistance (AMR) is a global health problem threatening safe, effective healthcare delivery in all countries and settings. The ability of microorganisms to become resistant to the effects of antimicrobials is an inevitable evolutionary process. The misuse and overuse of antimicrobial agents have increased the importance of a global focus on antimicrobial stewardship (AMS). This review provides insight into the current AMS landscape and identifies contemporary actors and initiatives related to AMS projects in eight African countries (Ghana, Kenya, Malawi, Nigeria, Sierra Leone, Tanzania, Uganda, and Zambia), which form a network of countries participating in the Commonwealth Partnerships for Antimicrobial Stewardship (CwPAMS) programme. We focus on common themes across the eight countries, including the current status of AMR, infection prevention and control, AMR implementation strategies, AMS, antimicrobial surveillance, antimicrobial use, antimicrobial consumption surveillance, a one health approach, digital health, pre-service and in-service AMR and AMS training, access to and supply of medicines, and the impact of COVID-19. Recommendations suitable for adaptation are presented, including the development of a national AMS strategy and incorporation of AMS in pharmacists' and other healthcare professionals' curricula for pre-service and in-service training.

Effectiveness of a structured stimulated spontaneous safety monitoring of medicines reporting program in strengthening pharmacovigilance system in Tanzania.

Under-reporting of adverse drug events (ADEs) is a challenge facing developing countries including Tanzania. Given the high magnitude of under-reporting, it was necessary to develop and assess the effectiveness of a 'structured stimulated spontaneous safety monitoring' (SSSSM) reporting program of ADEs which aimed at strengthening pharmacovigilance system in Tanzania. A quasi-experimental design and data mining technique were used to assess the effect of intervention after the introduction of program in seven tertiary hospitals. ADEs reports were collected from a single group and compared for 18 months before (July 2017 to December, 2018) and after the program (January 2019 to June 2020). Out of 16,557 ADEs reports, 98.6% (16,332) were reported after intervention and 0.1% (23) death related to adverse drug reactions (ADRs) were reported. Reports increased from 20 to 11,637 after intervention in Dar es salaam, 49 to 316 in Kilimanjaro and 17 to 77 in Mbeya. The population-based reporting ratio per 1,000,000 inhabitants increased from 2 reports per million inhabitants in 2018 to 85 reports in 2019. The SSSSM program can increase the reporting rate of ADEs and was useful in detecting signals from all types of medicines. This was first effective developed spontaneous program to monitor medicine safety in Tanzania.

Longitudinal dynamics of SARS-CoV-2-specific cellular and humoral immunity after natural infection or BNT162b2 vaccination.

The timing of the development of specific adaptive immunity after natural SARS-CoV-2 infection, and its relevance in clinical outcome, has not been characterized in depth. Description of the long-term maintenance of both cellular and humoral responses elicited by real-world anti-SARS-CoV-2 vaccination is still scarce. Here we aimed to understand the development of optimal protective responses after SARS-CoV-2 infection and vaccination. We performed an early, longitudinal study of S1-, M- and N-specific IFN-γ and IL-2 T cell immunity and anti-S total and neutralizing antibodies in 88 mild, moderate or severe acute COVID-19 patients. Moreover, SARS-CoV-2-specific adaptive immunity was also analysed in 234 COVID-19 recovered subjects, 28 uninfected BNT162b2-vaccinees and 30 uninfected healthy controls. Upon natural infection, cellular and humoral responses were early and coordinated in mild patients, while weak and inconsistent in severe patients. The S1-specific cellular response measured at hospital arrival was an independent predictive factor against severity. In COVID-19 recovered patients, four to seven months post-infection, cellular immunity was maintained but antibodies and neutralization capacity declined. Finally, a robust Th1-driven immune response was developed in uninfected BNT162b2-vaccinees. Three months post-vaccination, the cellular response was comparable, while the humoral response was consistently stronger, to that measured in COVID-19 recovered patients. Thus, measurement of both humoral and cellular responses provides information on prognosis and protection from infection, which may add value for individual and public health recommendations.

Practical Pharmacist-Led Interventions to Improve Antimicrobial Stewardship in Ghana, Tanzania, Uganda and Zambia.

The World Health Organisation (WHO) and others have identified, as a priority, the need to improve antimicrobial stewardship (AMS) interventions as part of the effort to tackle antimicrobial resistance (AMR). An international health partnership model, the Commonwealth Partnerships for Antimicrobial Stewardship (CwPAMS) programme, was established between selected countries in Africa (Ghana, Tanzania, Zambia and Uganda) and the UK to support AMS. This was funded by UK aid under the Fleming Fund and managed by the Commonwealth Pharmacists Association (CPA) and Tropical Health and Education Trust (THET). The primary aims were to develop local AMS teams and generate antimicrobial consumption surveillance data, quality improvement initiatives, infection prevention and control (IPC) and education/training to reduce AMR. Education and training were key components in achieving this, with pharmacists taking a lead role in developing and leading AMS interventions. Pharmacist-led interventions in Ghana improved access to national antimicrobial prescribing guidelines via the CwPAMS mobile app and improved compliance with policy from 18% to 70% initially for patients with pneumonia in one outpatient clinic. Capacity development on AMS and IPC were achieved in both Tanzania and Zambia, and a train-the-trainer model on the local production of alcohol hand rub in Uganda and Zambia. The model of pharmacy health partnerships has been identified as a model with great potential to be used in other low and middle income countries (LMICs) to support tackling AMR.

Returning of antiretroviral medication dispensed over a period of 8 months suggests non-adherence despite full adherence according to real time medication monitoring.

Real-time medication monitoring (RTMM) may potentially enhance adherence to antiretroviral treatment (ART). We describe a participant in an ongoing trial who, shortly after completing trial participation, died of cryptococcal meningitis despite high levels of adherence according to self-report, pill-counts and RTMM (> 99%). However, she evidenced consistently high HIV viral load throughout the 48-week study follow-up. Subsequently, her relatives unsolicitedly returned eight months' dispensed ART medication that she was supposed to have taken. This brief report illustrates the challenges of adherence measurements including RTMM, and reinforces the need to combine adherence assessments with viral load monitoring in HIV care.

Technical and Psychosocial Challenges of mHealth Usage for Antiretroviral Therapy Adherence Among People Living With HIV in a Resource-Limited Setting: Case Series.

BACKGROUND: Mobile communication has been found to improve antiretroviral therapy (ART) adherence among people living with HIV. In an ongoing randomized clinical trial, 2 mobile communication strategies (ie, sending SMS text messages and real-time medication monitoring [RTMM]) were used to improve adherence to ART among people living with HIV in Tanzania. We noticed remarkable discrepancies between self-reported adherence and adherence recorded by SMS text messaging or RTMM among some of the first trial participants. OBJECTIVE: Our objective was to describe these cases and the observed discrepancies in more detail, to serve as a useful illustration of some of the challenges in using mobile health in resource-limited settings. METHODS: In an ongoing randomized trial, adults living with HIV from two HIV treatment centers in Tanzania who were suspected of low levels of adherence were randomly assigned in a 1:1:1 ratio to receive (1) SMS text message reminders, (2) an RTMM device, or (3) no additional intervention to standard HIV care. During bimonthly study visits, the participants self-reported their level of adherence, received feedback about their level of adherence based on SMS text messaging or RTMM, and discussed strategies to overcome adherence problems with nurses providing HIV care. For the purpose of this report, we selected people living with HIV who had completed 5 follow-up visits and consistently reported more than 95% adherence, while SMS text messaging or RTMM recorded lower than 75% adherence. The participants were invited for a short, face-to-face in-depth interview to explore reasons for this discrepancy. RESULTS: At the time of this analysis, 26 participants had completed follow-up. Six of these evidenced the above-mentioned discrepancies, with an average adherence of 46% based on SMS text messaging or RTMM, while self-reported adherence was 98%. Five of these 6 participants insisted that their adherence to ART was good, with 4 reporting that their adherence to properly using the monitoring device was low. Three participants mentioned concerns about involuntary disclosure of HIV status as a main reason for low adherence to using the device. Two participants were still depending on other reminder cues despite receiving SMS text message or RTMM reminders. Poor network coverage caused low adherence in 1 participant. CONCLUSIONS: Psychosocial barriers were reported as importantly contributing to low adherence, both with respect to use of ART and proper use of the adherence-monitoring device. This case series illustrates that when introducing new digital adherence monitoring technology, researchers should consider psychosocial barriers and distinguish between adherence to device use and adherence to treatment. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201712002844286; https://tinyurl.com/y98q4p3l.

Awareness and Reporting of Antiretroviral Adverse Events Among Clients and Health-Care Providers at a Referral Hospital in Moshi, Northern Tanzania: A Cross-Sectional Study.

BACKGROUND: Pharmacovigilance is a means of ensuring drug safety, and thus it ensures that the risks associated with medication adminstration and consumption do not outweigh the benefits. Antiretroviral therapy (ART) for HIV care and treatment has reduced mortality and morbidity, but adverse drug reactions (ADRs), which can lead to treatment failure, remain a concern. In 2015 in Tanzania, 688,800 adults were taking ART. All health-care providers are required to report all suspected ADRs seen or reported by their patients using yellow forms available at all care and treatment centres in Tanzania. However, the actual practice of reporting is not taking place. This study aimed to explore the patients' knowledge and HIV/AIDS health-care providers' reporting of ART adverse events at Kilimanjaro Christian Medical Centre (KCMC). METHODS: A cross-sectional study using a semi-structured questionnaire was conducted between June and July 2016 within HIV, dermatology, and infectious disease clinics at KCMC. All health-care providers providing HIV services within these clinics completed a questionnaire. Means and standard deviations were used to summarise the numerical data with normal distributions (age of patients), while numerical data that were not normally distributed (duration on ART) were summarised using medians and ranges. Frequencies and percentages were used to summarise categorical variables. RESULTS: All 63 health-care providers agreed that ADR reporting was necessary. Forty-six (73%) were aware of the national ADR reporting system, but only 32 (50.8%) reported having received training on pharmacovigilance. Only 4 (6.3%) of all health-care providers reported always filling the ADR report forms; 27 (42.9%) rarely filled the forms, and 32 (50.8%) reported having never filled an ADR reporting form. Training on pharmacovigilance had a positive influence on ADR reporting. Lack of motivation, uncertainty about reporting procedures, lack of time, unavailability of reporting forms, and ignorance were the major factors affecting reporting among health-care providers. CONCLUSION: The majority of health-care providers were aware of the need and importance of ADR reporting and the national pharmacovigilance system. However, ART adverse events are underreported. More effort is needed to strengthen the continuous reporting of ADRs by providing continuous education to health-care providers; this will lead to their active participation in pharmacovigilance.

Evaluation of Prescriptions Dispensed in the Outpatient Pharmacies of a University Teaching Hospital in Moshi, Kilimanjaro Region, Tanzania: A Cross-Sectional Study.

BACKGROUND: Prescriptions written in daily medical practice are associated with increasing numbers of prescription writing errors. Both omission and commission errors are encountered and caused by prescribers of different cadres. Prescribing errors are associated with adverse drug events (ADEs), which are harmful to patients. This study aimed to determine the common prescription errors, the categories of prescribers who commit prescription errors, and the most prescribed drugs in the outpatient pharmacies in general practice at Kilimanjaro Christian Medical Centre (KCMC). METHODS: A prospective cross-sectional descriptive study was conducted at KCMC, a referral and teaching university hospital. All prescription dispensed on 2 June 2017 from the hospital's 2 outpatient pharmacies were reviewed, and our analysis determined the different types of prescription errors. A form designed by the authors was used to collect data from the prescription forms. RESULTS: A total of 242 prescriptions were studied, and the most common omission errors were missing patients' weight (n=231, 95.5%), missing patients' address (n=213, 88.0%), missing drug dosage (n=159, 67.1%), and commission errors were due to wrong drug strength (n=10, 2.0%). Intern doctors were leading in writing prescriptions with errors (n=352, 25.6%), followed by residents (n=199, 14.5%), registrar doctors (n=167, 12.1%), and specialists (n=45, 3.3%). The most commonly prescribed drugs were antibiotics (n=120, 17.3%), antihypertensives (n=81, 11.7%), and analgesics (n=86, 12.4%). CONCLUSION: There were significant prescription errors at the study site, hence an intervention is needed to improve skills of prescribers. Educational interventions can substantially contribute to minimising such errors. Initaiting programmes and short courses on prescription writing before medical internship at the health facility might also be helpful.

Reduction of nevirapine-driven HIV mutations by carbamazepine is modulated by CYP3A activity.

OBJECTIVES: The reduction in mother-to-child transmission of HIV-1 by single-dose nevirapine given at birth onset is achieved at the expense of de novo HIV-1 resistance mutations. In the VITA1 study, single-dose carbamazepine accelerated nevirapine elimination, but the accompanying trend towards fewer de novo HIV-1 mutations was statistically non-significant. METHODS: We investigated if the effect of carbamazepine was confounded by the individual variability in nevirapine metabolism and transport. RESULTS: Nine of 34 (26%) single-dose nevirapine-treated women had one or more nevirapine-associated resistance mutations, compared with 3 of 34 (9%) in the single-dose nevirapine/carbamazepine arm. The genetic polymorphisms in CYP2B6 and MRP7 affected neither nevirapine kinetics nor the development of HIV-1 resistance. In contrast, the reduction in HIV-1 mutations by single-dose carbamazepine reached statistical significance at P = 0.04 with an OR of 0.1 (95% CI 0.01-0.90) upon consideration of CYP3A activity, defined as the ratio of 4ß-hydroxycholesterol to cholesterol, and it was more likely in women with higher CYP3A activity. These findings were in agreement with CYP3A induction in carbamazepine-treated patients. Likewise, carbamazepine induced CYP3A4, but not CYP2B6, in vitro when combined with nevirapine. CONCLUSIONS: The induction of nevirapine elimination reduces HIV-1 resistance mutations, but this effect is modulated by individual CYP3A activity. The study suggests that CYP3A4 activity could be monitored using an endogenous marker and, if needed, boosted to improve clinical endpoints.

Nevirapine concentrations in saliva measured by thin layer chromatography and self-reported adherence in patients on antiretroviral therapy at Kilimanjaro Christian Medical Centre, Tanzania.

BACKGROUND: Thin layer chromatography (TLC) can be used to perform therapeutic drug monitoring in resource-limited settings, where more expensive analytical methods, such as high-performance liquid chromatography or liquid chromatography-mass spectrometry, are not feasible. OBJECTIVES: The aim of this cross-sectional study was to compare saliva concentrations of nevirapine (NVP) with self-reported adherence in patients on NVP-containing antiretroviral treatment at Kilimanjaro Christian Medical Centre, Moshi, Tanzania. METHODS: HIV-infected patients using a combination of zidovudine + lamivudine + NVP, or stavudine + lamivudine + NVP, for more than 4 weeks were included. Saliva samples were collected using dental cotton rolls impregnated with citric acid (20 mg). Saliva NVP concentrations were analyzed using TLC. Adherence to ARV medication was assessed by self-reporting using the Morisky scale. RESULTS: Of the 91 study participants, 79 (86.8%) had therapeutic saliva NVP concentrations (ie, >1.75 mg/L) and 12 (13.2%) had subtherapeutic concentrations. Self-reported adherence among the study participants was high in 62 participants (68.1%), moderate in 24 (26.4%), and low in 5 (5.5%). Fifty-seven (91.9%) of the study participants with high self-reported adherence had therapeutic saliva NVP concentrations. Of the 5 participants with low self-reported adherence, 3 had therapeutic NVP concentrations. CONCLUSIONS: A high proportion of patients had therapeutic NVP saliva concentrations as measured by TLC, which showed a good agreement with self-reported adherence.

Effect of 7 days of phenytoin on the pharmacokinetics of and the development of resistance to single-dose nevirapine for perinatal HIV prevention: a randomized pilot trial.

OBJECTIVES: To confirm whether 7 days of phenytoin, an enzyme inducer, would decrease the elimination half-life of single-dose nevirapine and to investigate its effect on the development of nevirapine resistance in pregnant, HIV-infected women. METHODS: In a pharmacokinetic pilot trial (NCT01187719), HIV-infected, antiretroviral (ARV)-naive pregnant women ≥18 years old from Zambia and Tanzania and with CD4 cell counts >350 cells/mm(3) were randomized 1 : 1 to a control (zidovudine pre-delivery, single-dose nevirapine/zidovudine/lamivudine at delivery and zidovudine/lamivudine for 7 days post-delivery) or an intervention (control plus 184 mg of phenytoin once daily for 7 days post-delivery) group. Primary endpoints were the pharmacokinetics of and resistance to nevirapine. RESULTS: Thirty-five and 37 women were allocated to the control and intervention groups, with median (IQR) ages of 27 (23-31) and 27 (23-33) years, respectively. Twenty-three and 23 women had detectable nevirapine levels at delivery and subsequent samples in the control and the intervention groups, respectively. Geometric mean (GM) (95% CI) plasma levels of nevirapine at delivery were 1.02 (0.58-1.78) mg/L and 1.14 (0.70-1.86) mg/L in the control and intervention groups, respectively (P = 0.76). One week after delivery, 0/23 (0%) and 15/22 (68%) control and intervention mothers, respectively, had undetectable levels of nevirapine (<0.05 mg/L; P<0.001). One week later, the figures were 10/21 (48%) and 18/19 (95%) mothers, respectively (P = 0.002). The GM (95% CI) half-life of nevirapine was 63.2 (52.8-75.7) versus 25.5 (21.6-30.1) h in the control group versus the intervention group (P < 0.001). New nevirapine mutations were found in 0/20 (0%) intervention-group mothers versus 1/21 (5%) control-group mothers. Overall, there was no difference in adverse events reported between the control and intervention arms (P > 0.28). CONCLUSIONS: Adding 7 days of an enzyme inducer to single-dose nevirapine to prevent mother-to-child transmission of HIV significantly reduced subtherapeutic nevirapine levels by shortening the half-life of nevirapine. As prolonged subtherapeutic nevirapine dosage leads to the emergence of resistance, single-dose nevirapine could be used with phenytoin as an alternative if other ARVs were unavailable.

Intrapartum single-dose carbamazepine reduces nevirapine levels faster and may decrease resistance after a single dose of nevirapine for perinatal HIV prevention.

BACKGROUND: World Health Organization guidelines recommend zidovudine + lamivudine for 7 days from labor onset in HIV-infected women receiving single-dose nevirapine (sdNVP) to cover prolonged subtherapeutic nevirapine concentrations. Although effective, this is complicated and does not eliminate resistance; alternative strategies could add benefit. METHODS: Antiretroviral-naive HIV-infected pregnant women aged 18-40 years, with CD4 >200 cells per cubic millimeter, able to regularly attend the antenatal clinics in Moshi, Tanzania, were enrolled 1:1 by alternate allocation to receive 200 mg sdNVP alone or in combination with open-label 400-mg single-dose carbamazepine (sdNVP/CBZ) at delivery (ClinicalTrials.gov NCT00294892). The coprimary outcomes were nevirapine plasma concentrations 1 week and nevirapine resistance mutations 6 weeks postpartum. Analyses were based on those still eligible at delivery. RESULTS: Ninety-seven women were assigned to sdNVP and 95 to sdNVP/CBZ during pregnancy, of whom 75 sdNVP and 83 sdNVP/CBZ were still eligible at delivery at study sites. The median (interquartile range) nevirapine plasma concentration was 1.55 (0.88-1.84) mg/L in sdNVP (n = 61) and 1.40 (0.93-1.97) mg/L in sdNVP/CBZ (n = 72) at delivery (P = 0.91), but 1 week later was significantly lower in sdNVP/CBZ [n = 63; 0.09 (0.05-0.20) mg/L] than in sdNVP [n = 52; 0.20 (0.09-0.31) mg/L; rank-sum: P = 0.004] (geometric mean ratio: 0.64, 95% confidence interval: 0.43 to 0.96; P = 0.03). Six weeks postpartum, nevirapine mutations were observed in 11 of 52 (21%) in sdNVP and 6 of 55 (11%) in sdNVP/CBZ (odds ratio = 0.46, 95% confidence interval: 0.16 to 1.34; P = 0.15). CONCLUSIONS: Addition of single-dose carbamazepine to sdNVP at labor onset in HIV-infected, pregnant women did not affect nevirapine plasma concentration at delivery, but significantly reduced it 1 week postpartum, with a trend toward fewer nevirapine resistance mutations.

Trombosis venosa portal y mesentérica asociadas a hiperhomocisteinemia y anemia perniciosa en un paciente heterocigoto para la mutación C677T del gen de la MTHFR / Portal and mesenteric vein thrombosis associated with hyperhomocysteinemia and pernicious anemia in a patient heterozygous for the MTHFR C677T mutation

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Therapeutic drug monitoring of nevirapine in resource-limited settings.

BACKGROUND: We developed a simple and inexpensive thin-layer chromatography (TLC) assay for semiquantitative detection of saliva concentrations of nevirapine in resource-limited settings. The method was validated in an African target population. METHODS: Paired plasma and saliva nevirapine concentrations were assayed by high-performance liquid chromatography (HPLC); saliva concentrations of nevirapine were also assayed by TLC. The rate of false-positive results was the proportion of subtherapeutic nevirapine saliva and plasma concentrations determined by HPLC that were judged to be therapeutic in saliva specimens by TLC. The rate of false-negative results was the proportion of therapeutic nevirapine saliva and plasma concentrations determined by HPLC that were judged to be subtherapeutic in saliva specimens by TLC. The extent of agreement in TLC readings between 5 technicians and 2 batches of TLC sheets was evaluated. RESULTS: Twenty-five (9%) of 286 African adults had a subtherapeutic plasma nevirapine concentration. The median ratio of nevirapine concentrations in saliva to those in plasma was 0.51:1. The rate of false-positive results for TLC was 0% (0 of 23 specimens) when TLC results were compared with HPLC results for saliva specimens and 8% (2 of 25 specimens) when TLC results were compared with HPLC results for plasma specimens. The rate of false-negative results for TLC was 1% (3 of 263 specimens) when TLC results were compared with HPLC results for saliva specimens and 1% (3 of 261 specimens) when TLC results were compared with HPLC results for plasma specimens. The extent of agreement of TLC results was substantial for the 5 technicians (Fleiss's kappa = 0.77) and for the 2 batches of sheets (Cohen's kappa = 0.80). CONCLUSIONS: The TLC assay was found to be sensitive, specific, and robust in the detection of subtherapeutic nevirapine concentrations in saliva specimens obtained from African HIV-infected adults. It is an attractive alternative to HPLC for therapeutic drug monitoring of nevirapine in resource-limited settings.