Protocol for active safety monitoring of a cohort of patients using a dolutegravir-based antiretroviral regimen in Mozambique

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Study Justification:
– The study aims to establish an active pharmacovigilance system to monitor adverse events in patients using a dolutegravir-based antiretroviral regimen in Mozambique.
– This monitoring system will support the effectiveness of Mozambique’s public health programs in improving the care and treatment outcomes for people with HIV/AIDS.
– The study is a response to concerns raised about a potential safety signal identified with dolutegravir in a previous study conducted in Botswana.
Study Highlights:
– This is a prospective, non-interventional, descriptive cohort study.
– The cohort consists of HIV-infected patients starting treatment with a dolutegravir-based regimen.
– The study will be conducted at 10 sentinel health centers in Mozambique.
– Patients will have routine follow-up visits for the first 3 months after starting treatment, and subsequently every 3 months for a total period of 1 year.
– Adverse events will be monitored and recorded during the follow-up period.
– The intended size of the cohort is 3000 patients.
Study Recommendations:
– Findings from the study will be reported to the Ministry of Health and participating health centers to inform policy and practice.
– Recommendations derived from the findings will be disseminated to healthcare providers and patients through information leaflets.
– Findings and recommendations will also be shared with a wider audience through the publication of scientific and professional articles in peer-reviewed journals.
Key Role Players:
– National Directorate of Pharmacy
– National Program for the Control of STI/HIV/AIDS
– National Commission on Bioethics in Health
– Ministry of Health
– Healthcare providers (clinicians, nurses, pharmacists, pharmacy technicians)
– Data entry personnel
– Data analysts
– Multistakeholder active monitoring committee
Cost Items for Planning Recommendations:
– Training of healthcare providers, data entry personnel, and data analysts
– Development and dissemination of information leaflets
– Data management tools and systems
– Supervisory visits and support
– Storage and archiving of data
– Publication costs (journal fees, article processing charges)
– Dissemination activities (newsletters, reports)

The strength of evidence for this abstract is 7 out of 10.
The evidence in the abstract is moderately strong. The study is described as a prospective, non-interventional, descriptive cohort study, which provides valuable information on the safety of a dolutegravir-based antiretroviral regimen in Mozambique. The study has a clear objective and methodology, including the size of the cohort and the follow-up period. Ethical approval and informed consent are mentioned, indicating adherence to ethical standards. However, the abstract lacks specific details on the data collection methods, statistical analysis, and potential limitations of the study. To improve the strength of the evidence, the abstract could include more information on the data collection tools, statistical methods used, and potential limitations of the study, such as selection bias or loss to follow-up. Additionally, providing information on the expected outcomes or objectives of the study would further enhance the clarity and usefulness of the abstract.

Introduction Dolutegravir-based antiretroviral therapy (ART) is increasingly being used as the preferred first-line regimen for the treatment of HIV in low-income and middle-income countries. The National Program for the Control of STI/HIV/AIDS in Mozambique has planned a phased introduction of the tenofovir/lamivudine/dolutegravir (TLD) regimen. In 2019, concerns about a potential safety signal identified with dolutegravir identified in the results of the Tsepamo study, conducted in Botswana, led the National Directorate of Pharmacy and the National Program for the Control of STI/HIV/AIDS to establish an active pharmacovigilance surveillance system among newly placed patients on a TLD regimen. This activity aims to establish an active pharmacovigilance system to monitor adverse events in patients on a TLD regimen to support the effectiveness of Mozambique’s public health programmes in improving the process of care and treatment outcomes for people with HIV/AIDS. Methods and analysis This is a prospective, non-interventional, descriptive cohort study to monitor HIV patients managed with TLD at 10 sentinel health centres in Mozambique. The cohort consists of HIV-infected patients commencing treatment with TLD, either as treatment naïve patients or switched from other ART regimens. Patients have monthly routine follow-up visits for the first 3 months after starting HIV treatment with TLD, and subsequently every 3 months for a total period of 1 year. Patients are monitored to identify possible adverse events during the follow-up period. The intended size of the cohort is 3000 patients. Ethics and dissemination Ethical approval was obtained from the National Commission on Bioethics in Health in Mozambique. Written informed consent is obtained from each participant who agrees to participate to have their information collected, analysed and stored. Findings will be reported to the Ministry of Health and participating health centres to inform policy and practice as well as disseminated by peer-review publications.

This is a prospective, non-interventional, observational cohort study of persons living with HIV who are newly placed on a TLD regimen at sentinel sites. The cohort consists of patients with a diagnosis of HIV, regardless of age and gender commencing treatment with TLD, either as treatment naïve patients or switched from another ARV regimen. Excluded from the cohort are those already taking or switched to TLD prior to commencement of active monitoring, patients who do not consent to be part of the active monitoring or those who are unable to provide a useful medical history for any reason. Patient enrolment commenced in April 2020. Healthcare providers (HCPs) at 10 sentinel sites are requested to enrol eligible patients into the cohort during treatment initiation visits. The intended size of the cohort is 3000 patients to be followed up during routine care visits over 12 months. This sample size provides a 95% chance of identifying AEs having an incidence of 1:1000.12 The presence or absence of AEs, as well as additional patient information, is recorded onto a pretested active surveillance data collection form (see online supplemental file annex 1). An AE is defined as ‘any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment’.13 HCPs are requested to monitor for and record the presence or absence of all AEs experienced by the patient during routine clinical care, including AEs of special interest (box 1). All pregnant women, including those who become pregnant during treatment with TLD, are monitored for pregnancy outcomes of interest and other AEs in accordance with the guidance for active monitoring of pregnant women on TLD (see online supplemental file annex 2). All events and medical conditions are coded using the Medical Dictionary for Regulatory Activities during data entry.14 bmjopen-2021-050671supp001.pdf Day ‘0’ is the day the patient is started on a TLD regimen and enrolled in the cohort for active monitoring. Each enrolled patient will be followed up for up to 12 months. Follow-up visits to monitor and document data on possible ADRs/AEs will be on a monthly basis for the first 3 months after commencement of HIV treatment with TLD per routine patient visit schedule. Subsequent follow-up visits for ADR/AE monitoring will be conducted every 3 months. Thus, each patient should have a minimum of six ADR/AE monitoring visits throughout the duration of the active surveillance programme. Patients are advised to return to the clinic even before their scheduled follow-up visit if they experience an AE. Alternatively, patients who are able to read and write may be given a paper copy of the follow-up questionnaire to write down AEs that they may have experienced before their next scheduled visit and instructed to bring those forms to their next visit. The National HIV/AIDS control program modified the routine visit schedule for the majority of stable patients on treatment during the COVID-19 lockdown period to quarterly visit. The follow-up schedule for monitored patients was modified accordingly. Women who become pregnant while on treatment with TLD or before beginning the TLD regimen will be monitored at each antenatal visit up to delivery and the mother and newborn up to 3 months postdelivery. Guidance on active monitoring for pregnant women on TLD (see online supplemental file annex 2) is based, in part, on the country’s experience with the Assessment of the Safety of Antimalarial Drug Use During Early Pregnancy study.15 A team of HCPs consisting of at least one designated clinician, a nurse and a pharmacist or pharmacy technician at each site was trained on standard operating procedures. Various methods are used to minimise loss to follow-up, such as follow-up phone calls or home visits to collect the necessary data from patients living in distant places from the sentinel site. The DNF is coordinating the operational implementation of the programme including the establishment and coordination of a national multistakeholder committee to guide and advise overall implementation. The multistakeholder committee consists of representatives from the DNF, HIV programme, TB programme, maternal and child health programme, and other stakeholders as determined by the DNF. The DNF in collaboration with the national HIV programme selected 10 facilities (table 1) to serve as sentinel sites based on the following criteria: Sentinel sites included in this active surveillance activity Each sentinel site is requested to enrol approximately 300 patients over a period of 6 months. Patients and the public were not involved in the design of this study. The active surveillance monitoring activity uses a combination of electronic and paper-based tools. Forms for initiation and follow-up were based, in part, on generic templates provided by WHO as well those used for active pharmacovigilance elsewhere in sub-Saharan Africa.9 16–22 The data collection forms are as follows: treatment initiation form (form A), follow-up visit form (form B) and birth outcome and newborn screening form (form C) (see online supplemental file annex 1). Data entry personnel at each site enters the data collected on the paper forms into an electronic data management tool—Pharmacovigilance Monitoring System and transmit the data to the DNF every week. Completed forms are retrieved from the sites during supervisory visits and submitted to the DNF for safekeeping and archiving. The multistakeholder active safety monitoring committee will use the WHO Uppsala Monitoring Centre causality assessment method to assess the AE reports to determine the relationship between reported AEs and medicine(s) taken by patients.23 The committee will classify AEs into two groups: Group 1: events determined as having a certain, probable or possible relationship with the monitored medicine. These will be classified as ‘adverse drug reactions’ because they are likely to be related to the use of the monitored medicine and entered into the national ADR database. Group 2: events determined as having an unlikely or unassessable relationship with medicine use. These will be classified as ‘incidentals’ as their occurrence is likely to be incidental to the use of the monitored medicine. These will be maintained in the active monitoring database. The DNF will add AEs assessed as having a certain, probable or possible relationship with the use of TLD to the national database of ADRs that are received through the spontaneous reporting system. All reported AEs that are assessed as having an unlikely relationship with the use of TLD will be left in the database of reports from the active monitoring system. The DNF will periodically analyse the data (monthly at the initial stage and quarterly thereafter) and generate descriptive frequency tables for demographics, medicine use and adverse medicine events. A mid-term (approximately 6–8 months after commencement of active monitoring) interim analysis and the main analysis at the conclusion of the follow-up period will be performed to determine adverse reaction profiles. The incidence of an ADR and AE will be calculated as the number of events divided by the total number of patient-months of follow-up. These estimates will be determined with 95% CIs assuming a Poisson distribution. Stratification and adjustments will be made as appropriate using collected baseline information, including comedication and comorbidities as collected through the data collection forms. Frequencies of ADRs will be compared by medicine category using univariate analysis and expressed as relative risks with corresponding 95% CIs and population attributable risk by ART and other medicines. HCPs, data entry personnel and data analysts involved in the process were trained on how to use the data collection tools and other aspects of active monitoring. Initial support supervision was conducted at each facility via phone calls within the first 2 months of patient enrolment. Further routine support supervision is provided to the sites monthly via phone calls due to COVID-19 restrictions. Quarterly in-person visits will commence in 2021. The DNF reviews the reports collected regularly for data quality and provide the necessary feedback for improving the quality of collected data. Written informed consent is obtained from each participant who consents to participate and have his or her information collected, analysed and stored. In addition, patients are informed that their participation in the programme is voluntary and they have the right to withdraw at any time and continue to receive care at the facility. Those who are between the ages of 12 and 18 years are required to sign an assent form to participate in the programme. In the event of children who are more than 30 kg and less than 12 years old, informed written consent is obtained from their parents. Confidentiality of patient data is maintained by limiting access to the information contained in the paper and electronic tools to only persons involved in the active monitoring of patients and who need to access the data for purposes of data entry, review or analysis. The DNF will enforce appropriate data access control measures and deidentify all data before sharing. Data from this active safety monitoring study will be stored by the DNF for 5 years after the programme ends. Findings from the TLD active monitoring activity will be disseminated to relevant stakeholders through quarterly newsletters or reports. The DNF, in collaboration with the multistakeholder active monitoring committee and with support from MTaPS, will develop, review and disseminate the newsletter or report. The DNF will use information leaflets to inform HCPs and patients of the recommendations derived from the findings. Findings and recommendations from the activity will also be shared with a wider audience through the publication of scientific and professional articles in peer-reviewed journals following due process. The 2019 guidelines from WHO provide reassurance of DTG as the preferred ARV drug in first and second-line regimens due to the declining estimate of NTD risk and observed efficacy.24 Major factors that can influence the transition to DTG include active surveillance of emerging toxicity issues and systems for monitoring safety in pregnancy.

The innovation described in the provided text is the establishment of an active pharmacovigilance surveillance system to monitor adverse events in patients using a dolutegravir-based antiretroviral regimen in Mozambique. This system aims to improve the process of care and treatment outcomes for people with HIV/AIDS. The key components of this innovation include:

1. Prospective Cohort Study: The implementation of a prospective, non-interventional, descriptive cohort study to monitor HIV patients managed with the dolutegravir-based regimen at 10 sentinel health centers in Mozambique. The cohort consists of both treatment-naive patients and those switched from other antiretroviral therapy regimens.

2. Active Monitoring: Patients enrolled in the cohort have routine follow-up visits, initially monthly for the first 3 months and subsequently every 3 months for a total period of 1 year. During these visits, healthcare providers monitor and record any adverse events experienced by the patients.

3. Patient Enrollment and Consent: Healthcare providers at the sentinel sites are responsible for enrolling eligible patients into the cohort during treatment initiation visits. Written informed consent is obtained from each participant who agrees to participate and have their information collected, analyzed, and stored.

4. Data Collection and Analysis: A combination of electronic and paper-based tools is used for data collection, including treatment initiation forms, follow-up visit forms, and birth outcome and newborn screening forms. Data entry personnel enter the collected data into an electronic data management tool. The data is periodically analyzed to generate descriptive frequency tables for demographics, medicine use, and adverse events.

5. Multistakeholder Committee: A national multistakeholder committee, consisting of representatives from various programs and stakeholders, is established to guide and advise the overall implementation of the active safety monitoring system.

6. Dissemination of Findings: Findings from the monitoring activity are reported to the Ministry of Health and participating health centers to inform policy and practice. They are also disseminated through peer-reviewed publications, newsletters, and information leaflets for healthcare providers and patients.

These innovations aim to improve access to maternal health by ensuring the safety and effectiveness of the dolutegravir-based antiretroviral regimen for pregnant women and other patients with HIV/AIDS in Mozambique.
AI Innovations Description
The recommendation to improve access to maternal health based on the described protocol is to establish an active pharmacovigilance system for monitoring adverse events in pregnant women using the dolutegravir-based antiretroviral regimen (TLD) in Mozambique. This recommendation aims to support the effectiveness of Mozambique’s public health programs in improving the process of care and treatment outcomes for pregnant women with HIV/AIDS.

The protocol outlines a prospective, non-interventional, observational cohort study that will monitor HIV patients managed with TLD at 10 sentinel health centers in Mozambique. The cohort will consist of HIV-infected pregnant women who are newly placed on a TLD regimen, either as treatment-naive patients or those switched from other antiretroviral therapy regimens. These patients will have routine follow-up visits during their pregnancy and up to 3 months post-delivery to monitor for possible adverse events.

The study will enroll approximately 3000 pregnant women and collect data on adverse events experienced during the follow-up period. The data will be recorded using a pretested active surveillance data collection form and entered into an electronic data management tool. A multistakeholder committee will assess the adverse event reports and classify them into adverse drug reactions or incidentals. The findings will be reported to the Ministry of Health and participating health centers to inform policy and practice. They will also be disseminated through peer-reviewed publications and newsletters to relevant stakeholders.

By implementing this active pharmacovigilance system, Mozambique can closely monitor the safety of the dolutegravir-based antiretroviral regimen in pregnant women and make informed decisions to ensure the well-being of both the mothers and their babies. This recommendation will contribute to improving access to maternal health by providing valuable data on the safety profile of TLD and guiding healthcare providers in delivering effective care to pregnant women with HIV/AIDS.
AI Innovations Methodology
The provided text describes a protocol for active safety monitoring of patients using a dolutegravir-based antiretroviral regimen in Mozambique. While this information is valuable, it does not directly relate to innovations for improving access to maternal health. However, I can provide you with some potential recommendations for innovations in maternal health and a brief methodology to simulate their impact.

1. Telemedicine: Implementing telemedicine services can improve access to maternal health by allowing pregnant women to receive remote prenatal care, consultations, and monitoring. This innovation can be achieved by developing mobile applications or online platforms that connect pregnant women with healthcare providers.

2. Community-based care: Establishing community-based care programs can enhance access to maternal health services, especially in remote or underserved areas. This approach involves training community health workers to provide basic prenatal care, education, and referrals to pregnant women in their communities.

3. Mobile clinics: Deploying mobile clinics equipped with essential maternal health services can reach women in rural or isolated areas who lack access to healthcare facilities. These clinics can provide prenatal care, screenings, vaccinations, and other necessary services.

4. Health information systems: Developing robust health information systems that capture and analyze maternal health data can improve access to care. These systems can help identify gaps in service delivery, monitor health outcomes, and inform evidence-based decision-making.

Methodology to simulate the impact of these recommendations on improving access to maternal health:

1. Define the target population: Determine the specific population that will benefit from the innovation, such as pregnant women in a particular region or community.

2. Collect baseline data: Gather data on the current state of maternal health access in the target population, including factors such as distance to healthcare facilities, availability of services, and utilization rates.

3. Develop a simulation model: Create a simulation model that incorporates the recommended innovations and their potential impact on improving access to maternal health. This model should consider factors such as the number of telemedicine consultations, the coverage of community-based care programs, the frequency of mobile clinic visits, and the effectiveness of health information systems.

4. Input data and parameters: Input the collected baseline data and relevant parameters into the simulation model. This includes information on the target population size, geographical distribution, healthcare infrastructure, and resources available for implementing the innovations.

5. Run simulations: Run multiple simulations using different scenarios and assumptions to assess the potential impact of the innovations on improving access to maternal health. This can involve varying parameters such as the scale of implementation, the reach of the innovations, and the expected utilization rates.

6. Analyze results: Analyze the simulation results to determine the projected improvements in access to maternal health. This can include metrics such as the increase in the number of women receiving prenatal care, the reduction in travel distances to healthcare facilities, and the improvement in health outcomes.

7. Validate findings: Validate the simulation findings by comparing them with real-world data or conducting pilot studies to assess the actual impact of implementing the recommended innovations.

8. Refine and iterate: Based on the simulation results and validation findings, refine the recommendations and iterate the simulation model to further optimize the impact on improving access to maternal health.

By following this methodology, policymakers and healthcare providers can assess the potential benefits and feasibility of implementing innovations to improve access to maternal health before investing resources in their implementation.

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