Adverse Events to SARS-CoV-2 (COVID-19) Vaccines and Policy Considerations that Inform the Funding of Safety Surveillance in Low- and Middle-Income Countries: A Mixed Methods Study.

INTRODUCTION/OBJECTIVE: Rapid global approval of coronavirus disease 2019 (COVID-19) vaccines and concurrent introduction in high-income countries and low- and middle-income countries (LMIC) highlights the importance of equitable safety surveillance of adverse events following immunization (AEFIs). We profiled AEFIs to COVID-19 vaccines, explored reporting differences between Africa and the rest of the world (RoW), and analyzed policy considerations that inform strengthening of safety surveillance in LMICs. METHODS: Using a convergent mixed-methods design we compared the rate and profile of COVID-19 vaccines' AEFIs reported to VigiBase by Africa versus the RoW, and interviewed policymakers to elicit considerations that inform the funding of safety surveillance in LMICs. RESULTS: With 87,351 out of 14,671,586 AEFIs, Africa had the second-lowest crude number and a reporting rate of 180 adverse events (AEs) per million administered doses. Serious AEs (SAEs) were 27.0%. Death accounted for about 10.0% of SAEs. Significant differences were found in reporting by gender, age group, and SAEs between Africa and the RoW. AstraZeneca and Pfizer BioNTech vaccines were associated with a high absolute number of AEFIs for Africa and RoW; Sputnik V contributed a considerably high rate of AEs per 1 million administered doses. Funding decisions for safety surveillance in LMICs were not based on explicit policies but on country priorities, perceived utility of data, and practical implementation issues. CONCLUSION: African countries reported fewer AEFIs relative to the RoW. To enhance Africa's contribution to the global knowledge on COVID-19 vaccine safety, governments must explicitly consider safety monitoring as a priority, and funding organizations need to systematically and continuously support these programs.

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

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.

Severe cutaneous adverse drug reactions manifesting as Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the national pharmacovigilance center in Nigeria: a database review from 2004 to 2017.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions (SCARs). There is scant literature on the characteristics and causes of these conditions among the Nigerian population. Here, we describe the epidemiology, associated morbidity and mortality, and culpable drugs in SJS and TEN cases using the National Pharmacovigilance (NPC) database in Nigeria. METHODS: A retrospective review of the NPC database was done to analyze SJS and TEN cases reported over a period of 14 years. Annual reports, age and sex of patients, type of reporter, suspects and concomitant drugs, time to onset (TTO) of the reactions, and outcome of SJS and TEN were evaluated. RESULTS: The NPC received a total of 24,015 adverse drug reaction (ADR) reports. SJS and TEN accounted for 284 (0.1%) of the total reports, of which 254 (89.4%) were SJS and the remainder were TEN. Females (n = 184, 64.8%) and individuals aged 19-40 years (n = 181, 63.7%) were the most affected by SJS and TEN. Antiretrovirals, followed by antibiotics, were the most common drug classes reported to cause SJS and TEN, with nevirapine (n = 174, 40.7%) and co-trimoxazole (n = 143, 33.5%) being the most widely implicated drugs. Among patients with reported outcomes, 73 (28.7%) SJS and 3 (10.0%) TEN cases recovered without sequelae, at the time of reporting. Severity of the SCAR was reported for only 171 (69.0%) cases, of which 12 (4.7%) and 8 (26.7%) resulted in death (Grade 5) among SJS and TEN cases, respectively. CONCLUSIONS: Antiretroviral and antibiotics were the commonly reported offending group of drugs for SJS and TEN cases. Nevirapine and co-trimoxazole were the commonly reported suspect drugs. SJS and TEN were reported most frequently in females and in patients aged 19-40 years, indicating that drug surveillance and counseling in these groups of patients may be beneficial.

A Retrospective Review of Serious Adverse Drug Reaction Reports in the Nigerian VigiFlow Database from September 2004 to December 2016.

BACKGROUND: Adverse drug reactions (ADRs) are a source of concern in healthcare as they negatively affect patients. Serious adverse drug reactions (SADRs) have an even greater impact on patients and the system in terms of morbidity and financial burden. The establishment of National Pharmacovigilance Centers (NPCs) has enhanced ADR reporting in Africa. The Nigerian Pharmacovigilance Centre has been collecting ADR reports using VigiFlow since 2004. OBJECTIVE: The aim of this study was to identify and analyze SADR reports in the Nigerian VigiFlow database in order to profile the patients with SADRs, the medicines most implicated, system organ classes (SOCs) affected, outcome of such reactions, including fatalities, and ADR reporting trends over the years. We also looked at the data elements provided in the reports as a proxy measure of report quality. METHOD: We retrospectively assessed all individual case safety reports (ICSRs) received by the NPC in Nigeria and entered into VigiFlow as SADR reports between September 2004 and December 2016. We defined SADR as any untoward reaction to any medicine dose that resulted in death, required in-patient hospitalization or prolongation of existing hospitalization, resulted in congenital anomaly, persistent or significant disability/incapacity or was life-threatening. The suspected SADRs were analyzed at the Medical Dictionary for Regulatory Activities SOC and Preferred Term levels. RESULTS: A total of 11,222 ICSRs were entered into VigiFlow during the study period, of which 298 (3%) were classified as SADR reports. Adults were the most affected (244/282; 87%). The median number of medicines per report was 3 (interquartile range = 2-4.75). Nevirapine (36/336; 11%), as a single entity, was the most reported medicine. Human immunodeficiency virus (HIV) infection affected 128/232 (55%) of those with SADRs. There was no statistically significant association between the number of reactions per report and sex of the patients (p = 0.280), their age groups (p = 0.670), or the number of medicines per report (p = 0.640). Hospitalization was the most frequently cited reason for classifying a report as serious (151/276; 53%) and death was reported in 48 cases (48/283; 17%). Based on the SOC, skin and subcutaneous tissue disorders (139/550; 25%) was the most affected, while anemia (55/550; 10%) was the most reported specific reaction. A substantial number of patients (107/256; 42%) either recovered fully or were recovering from the SADRs. The number of SADR reports received varied by year with no consistent trend. CONCLUSION: There is under-reporting of ADRs in the Nigerian VigiFlow® database, particularly SADRs and those involving pediatric and geriatric age groups. Given that over half of the SADR reports involved antiretroviral drugs, it is imperative to increase the surveillance of ADRs related to this class of drugs through regular clinical assessment of reports and provision of feedback on the findings to healthcare providers. Direct consumer reporting should also be encouraged as a means of increasing ADR reporting.

Addressing the under-reporting of adverse drug reactions in public health programs controlling HIV/AIDS, Tuberculosis and Malaria: A prospective cohort study.

BACKGROUND: Adverse Drug Reactions (ADRs) are a major clinical and public health problem world-wide. The prompt reporting of suspected ADRs to regulatory authorities to activate drug safety surveillance and regulation appears to be the most pragmatic measure for addressing the problem. This paper evaluated a pharmacovigilance (PV) training model that was designed to improve the reporting of ADRs in public health programs treating the Human Immunodeficiency Virus (HIV), Tuberculosis (TB) and Malaria. METHODS: A Structured Pharmacovigilance and Training Initiative (SPHAR-TI) model based on the World Health Organization accredited Structured Operational Research and Training Initiative (SOR-IT) model was designed and implemented over a period of 12 months. A prospective cohort design was deployed to evaluate the outcomes of the model. The primary outcomes were knowledge gained and Individual Case Safety Reports (ICSR) (completed adverse drug reactions monitoring forms) submitted, while the secondary outcomes were facility based Pharmacovigilance Committees activated and health facility healthcare workers trained by the participants. RESULTS: Fifty-five (98%) participants were trained and followed up for 12 months. More than three quarter of the participants have never received training on pharmacovigilance prior to the course. Yet, a significant gain in knowledge was observed after the participants completed a comprehensive training for six days. In only seven months, 3000 ICSRs (with 100% completeness) were submitted, 2,937 facility based healthcare workers trained and 46 Pharmacovigilance Committees activated by the participants. Overall, a 273% increase in ICSRs submission to the National Agency for Food and Drug Administration and Control (NAFDAC) was observed. CONCLUSION: Participants gained knowledge, which tended to increase the reporting of ADRs. The SPHAR-TI model could be an option for strengthening the continuous reporting of ADRs in public health programs in resource limited settings.

Adverse reactions to fluoroquinolones in the Nigerian population: an audit of reports submitted to the National Pharmacovigilance Centre from 2004 to 2016.

Adverse drug reactions (ADRs) recorded in national pharmacovigilance databases in developed countries have been analyzed. However, adverse reactions to fluoroquinolones were observed globally despite their wide use and safety concerns. We provided information on the pattern of adverse reactions to fluoroquinolones reported spontaneously to the National Pharmacovigilance Centre (NPC), Nigeria. ADRs to fluoroquinolones reported to the NPC, over a period of 12 years, were analyzed. Evaluation was done for annual reports, age and gender of patients, type of reporter, suspected fluoroquinolones and adverse reactions, onset and outcome of ADRs, and causality. A total of 18527 ADR reports were received by the NPC. Antibiotics accounted for 1371(7.4%) of the total reports and fluoroquinolones accounted for 256 (18.7%) cases. A total of 540 ADRs due to fluoroquinolones was experienced by the patients. Multiple ADRs were experienced by 165 (65%) patients. Norfloxacin (2; 0.8%), moxifloxacin (3; 1.2%), ofloxacin (10; 3.9%), ciprofloxacin (112; 43.8%), and levofloxacin (129; 50.4%) were responsible for the ADRs. Neurological disorders (121; 22.4%), gastrointestinal disorders (118; 21.9%), and skin-appendage disorders (116; 21.5%) were the most reported ADRs, while pruritus (41; 7.6%), abdominal pain (34; 6.3%), vomiting (34; 6.3%), and skin rash (27; 5.0%) were the most frequently reported specific ADRs. Thirty-four (6.4%) patients experienced serious ADRs. Fluoroquinolones accounted for a small but significant proportion of ADRs spontaneously reported to the NPC in Nigeria. Ciprofloxacin and levofloxacin were the two most culpable fluoroquinolones due to their inappropriate use or increased use in multi-drug resistant tuberculosis (MDR-TB) treatment.

Impact of comorbidity on adverse drug reaction profile in a cohort of patients treated with Artemisinin combination therapies for uncomplicated malaria in Nigeria.

Artemisinin-based combination antimalarial therapy (ACTs), is still highly effective in uncomplicated falciparum malaria, however, there remain some concerns in relation to its safety and tolerability. Comorbid disease conditions may influence susceptibility to adverse drug reactions (ADRs) as the presence of multiple disease conditions may predisposes patients to ADRs due to the use of many medicines. There is therefore need to assess the impact of comorbidities on the ADR profile of malaria patients treated with ACTs. The study was carried out in health care facilities spread across Nigeria. From the database of over 10,000 patients recruited into an initial cohort, data for 1000 patients with comorbidities was extracted and matched with a control group of 1000 randomly selected patients with no comorbidity. There were 1105 adverse drug reactions in all, of which 66.2% were recorded in patients with comorbidity, and 34% are patients without comorbidity. The mean age of patients with comorbidities was 38.3 ± 17.5 years and 23.8 ± 17.2 for those without comorbidity. Out of the 979 patients with comorbidity, 36% were hypertensive, 2.2% hypertensive-diabetes, 16.4% peptic ulcer disease, 10.4% HIV/AIDS, 4.4% diabetes and 4.3% were asthmatic. Patients with comorbidity were three times more likely to have adverse drug reaction than those without comorbidity (Odds ration = 2.96; 95% CI = 2.23-3.93). HIV/AIDS and osteoarthritis were significantly associated with development of adverse drug reactions. Probability was <0.0001. Age, weight, and height of patients were also found to be risk factor for development of adverse drug reactions.