Monitoring and risk assessment of pesticide residues in selected herbal medicinal products in Ghana.

The high patronage of herbal medicinal products in Ghana for the treatment of diverse disease conditions raises concerns about patient safety, given that much of the raw materials for production are obtained from the wild or farmlands potentially exposed to varied agrochemical residues. Therefore, the work sought to investigate the contamination of herbal medicinal products with pesticide residues and assess the potential risk posed to patients. As a result, validated gas chromatography with mass spectrometry as a detector was used to determine forty-two pesticides in thirty herbal medicinal products. The performance parameters of the method such as linearity, accuracy, and precision were found as acceptable. Pesticide residues such as chlorpyrifos and/or bifenthrin were found in 4/30 herbal medicinal products. Specifically, 3/30 herbal medicinal products contained only one pesticide, while 1/30 was contaminated with both pesticide residues. The levels of pesticide residue contamination ranged between 2.5 and 5.0 µg/kg. The acute hazard quotient and chronic hazard quotient for the two pesticide residues were evaluated and ranged between 0.21 and 0.92% and between 8.21 × 10-4 and 5.88 × 10-3%. The detected pesticide residue levels are below the maximum residue limit values, which may not cause acute and chronic health risks due to intake of the selected herbal medicinal product. Nevertheless, patient safety and potential public health risk can be reduced by regular monitoring, and regulation of pesticide residue levels in herbal medicinal products.

Prescribing patterns and compliance with World Health Organization recommendations for the management of severe malaria: a modified cohort event monitoring study in public health facilities in Ghana and Uganda.

BACKGROUND: Injectable artesunate (AS) is the World Health Organization (WHO) recommended medication for the treatment of severe malaria followed with an oral artemisinin-based combination therapy (ACT). There are few studies indicating how physicians prescribe injectable AS, injectable quinine (Q) or injectable artemether (AR) and ACT for severe malaria. This study was undertaken to evaluate prescription compliance to the WHO recommendation in 8 public health facilities in Ghana and Uganda. This was a modified cohort event monitoring study involving patients who were administered with injectable anti-malarial for treatment of presumed or confirmed severe malaria. Patients prescribed at least one dose of injectable artesunate, artemether or quinine qualified to enrol in the study. Patients were recruited at inpatient facilities and followed up in the hospital, by phone or at home. Following WHO recommendations, patients are to be prescribed 3 doses of injectable AS, Q or AR for at least 24 h followed with oral ACT. Compliance rate was estimated as the number of patient prescriptions that met the WHO recommendation for treatment of severe malaria divided by the total number of patients who completed the study by end of follow up. Log-binomial regression model was used to identify predictors for compliance. Based on the literature and limitations of available data from the patients' record, the diagnosis results, age, gender, weight, and country were considered as potential predictors of prescriber adherence to the WHO recommendations. RESULTS: A total of 1191 patients completed the study, of which 93% were prescribed injectable AS, 3.1% (injectable AR or Q) with 32.5% prescribed follow-on oral ACT and 26% on concomitant antibiotics. 391 (32.8%) were in Ghana and 800 (67.2%) in Uganda. There were 582 (48.9%) women. The median age was 3.9 years (IQR = 2, 9) and median weight was 13 kg (IQR = 10, 20). Of the 1191 patients, 329 of the prescriptions complied with the WHO recommendation (compliance rate = 27.6%; 95% CI = [25.2, 30.2]). Diagnostic results (Adjusted prevalence ratio (aPR) = 4.56; 95% = [3.42, 6.08]; p < 0.0001) and weight (20 + kg vs < 10 kg: aPR = 0.65; 95% = [0.44, 0.96]; p = 0.015) were identified as factors independently associated with compliance. CONCLUSION: Injectable AS is the most commonly prescribed medicine in the management of severe malaria in Ghana and Uganda. However, adherence to the WHO recommendation of at least 3 doses of injectable anti-malarial in 24 h followed by a full course of ACT is low, at less than 30%.

The contribution of Ghanaian patients to the reporting of adverse drug reactions: a quantitative and qualitative study.

BACKGROUND: Under-reporting of adverse drug reactions (ADRs) is a major challenge for pharmacovigilance in Africa. This study sets out to assess the level of awareness of Ghanaian patients about ADRs and ADR-reporting and explores how different patients in Ghana recognize an ADR and the steps they take when they experience an ADR. METHODS: This was a two-part study consisting of a survey to quantify the awareness of Ghanaian patients on ADRs and ADR-reporting, and in-depth interviews to explore how patients recognize an ADR and the steps they take thereafter. Participants were selected from 28 health care facilities (HCF) in rural and urban areas in 4 out of the 10 administrative regions of Ghana. Chi-square tests were used to examine associations between demographic variables and i) awareness of ADRs and ADR-reporting, ii) ADR experience and iii) awareness of the Ghana Food and Drug Authority (Ghana-FDA) and its patient reporting system (PRS). Only participants that indicated they experienced an ADR were included for the in-depth interviews. Data was investigated for participants' awareness of ADRs, ADR reporting and steps taken when they experience ADRs. RESULTS: Of the total 572 participants enrolled in the study, 14% indicated they were unaware of ADRs and were excluded. Of the remaining 491 participants, 38% had experienced an ADR, of which 67% reported the ADR, 68% of them reported it to a doctor. Only 3% of the 491 participants were aware of the Ghana-FDA's PRS. The interview phase consisted of 33 patients who had experienced an ADR. Three key findings from the interview phase were; most participants recognized an ADR themselves, the symptoms of the ADR were the most mentioned reason for reporting and participants experienced a wide variety of obstacles in ADR-reporting. CONCLUSIONS: Most Ghanaian patients appear unaware of or unable/unwilling to use formal national channels for ADR reporting like the Ghana-FDA PRS. Motivation for ADR reporting appeared mainly personal and not communal. These findings warrant further attention in order to increase patient reporting of ADRs.

Adverse events and adherence to HIV post-exposure prophylaxis: a cohort study at the Korle-Bu Teaching Hospital in Accra, Ghana.

BACKGROUND: There is strong evidence that post-exposure prophylaxis (PEP) with antiretroviral drugs in the timely management of occupational exposures sustained by healthcare workers decreases the risk of HIV infection and PEP is now widely used. Antiretroviral drugs have well documented toxicities and produce adverse events in patients living with HIV/AIDS. In the era of "highly active antiretroviral therapy", non-adherence to treatment has been closely linked to the occurrence of adverse events in HIV patients and this ultimately influences treatment success but the influence of adverse events on adherence during PEP is less well studied. METHODS: Following the introduction of a HIV post-exposure prophylaxis program in the Korle-Bu Teaching Hospital in January 2005, the incidence of adverse events and adherence were documented in occupationally-exposed healthcare workers (HCWs) and healthcare students (HCSs). Cohort event monitoring was used in following-up on exposed HCWs/HCSs for the two study outcomes; adverse events and adherence. All adverse events reported were grouped by MedDRA system organ classification and then by preferred term according to prophylaxis regimen. Adherence was determined by the completion of prophylaxis schedule. Cox proportional regression analysis was applied to determine the factors associated with the cohort study outcomes. Differences in frequencies were tested using the Chi square test and p < 0.05 was considered statistically significant. RESULTS: A total of 228 exposed HCWs/HCSs were followed up during the study, made up of 101 exposed HCWs/HCSs administered lamivudine/zidovudine (3TC/AZT) for 3 days; 75 exposed HCWs/HCSs administered lamivudine/zidovudine (3TC/AZT) for 28 days; and 52 exposed HCWs/HCSs administered lamivudine/zidovudine/lopinavir-ritonavir (3TC/AZT/LPV-RTV) for 28 days. The frequency of adverse events was 28% (n = 28) in exposed HCWs/HCSs administered 3TC/AZT for 3 days, 91% (n = 68) in exposed HCWs/HCSs administered 3TC/AZT for 28 days and 96% (n = 50) in exposed HCWs/HCSs administered 3TC/AZT/LPV-RTV for 28 days. Nausea was the most commonly reported adverse events in all three regimens. Adherence was complete in all exposed HCWs/HCSs administered 3TC/AZT for 3days, 56% (n = 42) in exposed HCWs/HCSs administered 3TC/AZT for 28 days and 62% (n = 32) in exposed HCWs/HCSs administered 3TC/AZT/LPV-RTV for 28 days. In the Cox regression multi-variate analysis, exposed HCWs/HCSs administered 3TC/AZT for 3 days were 70% less likely to report adverse events compared with exposed HCWs/HCSs administered 3TC/AZT for 28 days (Adjusted HR = 0.30 [95% CI, 0.18-0.48], p < 0.001). Exposed HCWs/HCSs administered 3TC/AZT for 3 days were 75% more likely to adhere to the schedule compared with exposed HCWs/HCSs administered 3TC/AZT for 28 days (Adjusted HR = 1.75 [95% CI, 1.16-2.66], p = 0.008). CONCLUSION: The intolerance to adverse events was cited as the sole reason for truncating PEP, thereby indicating the need for adequate, appropriate and effective counselling, education, active follow-up (possibly through mobile /phone contact) and management of adverse events. Education on the need to complete PEP schedule (especially for exposed HCWs/HCSs on 28-day schedule) can lead to increased adherence, which is very critical in minimizing the risk of HIV sero-conversion. The present results also indicate that cohort event monitoring could be an effective pharmacovigilance tool in monitoring adverse events in exposed HCWs/HCSs on HIV post-exposure prophylaxis.

Predictors of antibiotics co-prescription with antimalarials for patients presenting with fever in rural Tanzania.

BACKGROUND: Successful implementation of malaria treatment policy depends on the prescription practices for patients with malaria. This paper describes prescription patterns and assesses factors associated with co-prescription of antibiotics and artemether-lumefantrine (AL) for patients presenting with fever in rural Tanzania. METHOD: From June 2009 to September 2011, a cohort event monitoring program was conducted among all patients treated at 8 selected health facilities in Ifakara and Rufiji Health and Demographic Surveillance System (HDSS). It included all patients presenting with fever and prescribed with AL. Logistic regression was used to model the predictors on the outcome variable which is co-prescription of AL and antibiotics on a single clinical visit. RESULTS: A cohort of 11,648 was recruited and followed up with 92% presenting with fever. Presumptive treatment was used in 56% of patients treated with AL. On average 2.4 (1 - 7) drugs was prescribed per encounter, indicating co-prescription of AL with other drugs. Children under five had higher odds of AL and antibiotics co-prescription (OR = 0.63, 95% CI: 0.46 - 0.85) than those aged more than five years. Patients testing negative had higher odds (OR = 2.22, 95% CI: 1.65 - 2.97) of AL and antibiotics co-prescription. Patients receiving treatment from dispensaries had higher odds (OR = 1.45, 95% CI: 0.84 - 2.30) of AL and antibiotics co-prescription than those served in health centres even though the deference was not statistically significant. CONCLUSION: Regardless the fact that Malaria is declining but due to lack of laboratories and mRDT in most health facilities in the rural areas, clinicians are still treating malaria presumptively. This leads them to prescribe more drugs to treat all possibilities.

Using classification tree modelling to investigate drug prescription practices at health facilities in rural Tanzania.

BACKGROUND: Drug prescription practices depend on several factors related to the patient, health worker and health facilities. A better understanding of the factors influencing prescription patterns is essential to develop strategies to mitigate the negative consequences associated with poor practices in both the public and private sectors. METHODS: A cross-sectional study was conducted in rural Tanzania among patients attending health facilities, and health workers. Patients, health workers and health facilities-related factors with the potential to influence drug prescription patterns were used to build a model of key predictors. Standard data mining methodology of classification tree analysis was used to define the importance of the different factors on prescription patterns. RESULTS: This analysis included 1,470 patients and 71 health workers practicing in 30 health facilities. Patients were mostly treated in dispensaries. Twenty two variables were used to construct two classification tree models: one for polypharmacy (prescription of ≥3 drugs) on a single clinic visit and one for co-prescription of artemether-lumefantrine (AL) with antibiotics. The most important predictor of polypharmacy was the diagnosis of several illnesses. Polypharmacy was also associated with little or no supervision of the health workers, administration of AL and private facilities. Co-prescription of AL with antibiotics was more frequent in children under five years of age and the other important predictors were transmission season, mode of diagnosis and the location of the health facility. CONCLUSION: Standard data mining methodology is an easy-to-implement analytical approach that can be useful for decision-making. Polypharmacy is mainly due to the diagnosis of multiple illnesses.

Genetic polymorphisms in MDR1, CYP3A4 and CYP3A5 genes in a Ghanaian population: a plausible explanation for altered metabolism of ivermectin in humans?

BACKGROUND: Ivermectin, a substrate of multidrug resistance (MDR1) gene and cytochrome P450 (CYP) 3A4, has been used successfully in the treatment of onchocerciasis in Ghana. However, there have been reports of suboptimal response in some patients after repeated treatment. Polymorphisms in host MDR1 and CYP3A genes may explain the observed suboptimal response to ivermectin. We genotyped relevant functional polymorphisms of MDR1 and CYP3A in a random sample of healthy Ghanaians and compared the data with that of ivermectin-treated patients with a view to exploring the relationship between suboptimal response to ivermectin and MDR1 and CYP3A allelic frequencies. METHODS: Using PCR-RFLP, relevant polymorphic alleles of MDR1 and CYP3A4 genes were analysed in 204 randomly selected individuals and in 42 ivermectin treated patients. RESULTS: We recorded significantly higher MDR1 (3435T) variant allele frequency in suboptimal responders (21%) than in patients who responded to treatment (12%) or the random population sample (11%). CYP3A4*1B, CYP3A5*3 and CYP3A5*6 alleles were detected at varied frequencies for the sampled Ghanaian population, responders and suboptimal responders to ivermectin. CYP3A5*1/CYP3A5*1 and CYP3A5*1/CYP3A5*3 genotypes were also found to be significantly different for responders and suboptimal responders. Haplotype (*1/*1/*3/*1) was determined to be significantly different between responders and suboptimal responders indicating a possible role of these haplotypes in treatment response with ivermectin. CONCLUSION: A profile of pharmacogenetically relevant variants for MDR1, CYP3A4 and CYP3A5 genes has been generated for a random population of 204 Ghanaians to address the scarcity of data within indigenous African populations. In 42 patients treated with ivermectin, difference in MDR1 variant allele frequency was observed between suboptimal responders and responders.

Pattern of drug utilization for treatment of uncomplicated malaria in urban Ghana following national treatment policy change to artemisinin-combination therapy.

BACKGROUND: Change of first-line treatment of uncomplicated malaria to artemisinin-combination therapy (ACT) is widespread in Africa. To expand knowledge of safety profiles of ACT, pharmacovigilance activities are included in the implementation process of therapy changes. Ghana implemented first-line therapy of artesunate-amodiaquine in 2005. Drug utilization data is an important component of determining drug safety, and this paper describes how anti-malarials were prescribed within a prospective pharmacovigilance study in Ghana following anti-malarial treatment policy change. METHODS: Patients with diagnosis of uncomplicated malaria were recruited from pharmacies of health facilities throughout Accra in a cohort-event monitoring study. The main drug utilization outcomes were the relation of patient age, gender, type of facility attended, mode of diagnosis and concomitant treatments to the anti-malarial regimen prescribed. Logistic regression was used to predict prescription of nationally recommended first-line therapy and concomitant prescription of antibiotics. RESULTS: The cohort comprised 2,831 patients. Curative regimens containing an artemisinin derivative were given to 90.8% (n = 2,574) of patients, although 33% (n = 936) of patients received an artemisinin-based monotherapy. Predictors of first-line therapy were laboratory-confirmed diagnosis, age >5 years, and attending a government facility. Analgesics and antibiotics were the most commonly prescribed concomitant medications, with a median of two co-prescriptions per patient (range 1-9). Patients above 12 years were significantly less likely to have antibiotics co-prescribed than patients under five years; those prescribed non-artemisinin monotherapies were more likely to receive antibiotics. A dihydroartemisinin-amodiaquine combination was the most used therapy for children under five years of age (29.0%, n = 177). CONCLUSION: This study shows that though first-line therapy recommendations may change, clinical practice may still be affected by factors other than the decision or ability to diagnose malaria. Age, diagnostic confirmation and suspected concurrent conditions lead to benefit:risk assessments for individual patients by clinicians as to which anti-malarial treatment to prescribe. This has implications for adherence to policy changes aiming to implement effective use of ACT. These results should inform education of health professionals and rational drug use policies to reduce poly-pharmacy, and also suggest a potential positive impact of increased access to testing for malaria both within health facilities and in homes.

Factors that influence the intention to use mobile phone caller tunes for patient reporting of adverse drug reactions: a qualitative study.

BACKGROUND: Patient reporting of adverse drug reactions (ADRs) is low in low- and middle-income countries, in part because of poor awareness to report. With the increase in mobile subscription, mobile phones can be used as a platform to disseminate information on ADRs. The aim of this study was to qualitatively assess the potential of using mobile phone caller tunes (the message or sound the caller hears before the receiver answers the call) to encourage patient reporting of ADRs. METHODS: A total of 38 key informant interviews and 12 focus group discussions (57 participants in groups of 4-5) were conducted in Accra, Ghana. The transcripts were analysed using key constructs of the Technology Acceptance Model (TAM) including perceived usefulness, perceived ease of use, and behavioural intention to use caller tunes for patient reporting of ADRs. RESULTS: Respondents mentioned lack of knowledge on reporting ADRs, and their willingness to use mobile phone caller tunes to promote patient reporting of ADRs. Many respondents pointed out how ADRs usually led to discontinuity in medication use, usually without consultation with health professionals. Caller tunes were regarded an innovative, accessible and convenient platform to disseminate information on ADRs. Most respondents intended to use caller tunes with drug safety information to promote ADR reporting, particularly to help their friends and family members. Simplicity of the message, use of songs or messages in local languages and price of downloading the caller tunes were important considerations. CONCLUSION: There is a need for the creation and testing of caller tunes on ADRs in Ghana to promote patient or consumer reporting of ADRs. Further studies are needed to assess factors that could influence the creation and use of caller tunes to disseminate information on drug safety.

Tenofovir-associated renal toxicity in a cohort of HIV infected patients in Ghana.

OBJECTIVE: Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue recommended in international HIV treatment guidelines. Purpose of this study was to estimate the long term effects of TDF on renal profile in a cohort of HIV patients in Ghana. Three hundred (300) consecutive HIV-positive patients who initiated TDF-based antiretroviral treatment in 2008 at the Korle-Bu Teaching Hospital were sampled. Creatinine clearance (CrCl) was calculated using the Cockcroft-Gault equation at baseline and renal impairment was defined as CrCl values of 30.0-49.9 mL/min (moderate renal impairment) and < 30 mL/min (severe renal impairment) as per institutional guidelines for renal function test. RESULTS: Median follow up time was 2.9 years (IQR 2.3-3.4 years). At study endpoint, 63 participants (21.0% [95% CI 6.5-26.1]) recorded CrCl rate below 50 mL/min indicating incident renal impairment, made up of 18.3% moderate renal impairment and 2.3% severe renal impairment. Factors associated with incidence of renal impairment were increasing age, decrease in creatinine clearance rate at baseline, WHO HIV stage III/IV and participants with BMI of < 18.5 kg/m2. Patients with identified renal impairment risk factors at ART initiation should be targeted and monitored effectively to prevent renal injury.

Safety Experience During Real-World Use of Injectable Artesunate in Public Health Facilities in Ghana and Uganda: Outcomes of a Modified Cohort Event Monitoring Study (CEMISA).

INTRODUCTION: Injectable artesunate (Inj AS) is the World Health Organization (WHO)-recommended product for treating severe malaria. However, despite widespread usage, there are few published safety studies involving large populations in real-world settings. In this study, we sought to assess the incidence of common adverse events (AEs) following the intake of Inj AS in real-life settings. METHODS: This is a modified cohort event monitoring study involving patients who were administered with Inj AS at eight sites (four each in Ghana and Uganda) between May and December 2016. Patients were eligible for inclusion if they had severe/complicated malaria and were able and willing to participate in the study. Eligible patients were followed up by telephone or hospital or home visit on Days 7, 14, 21 and 28 after drug administration to document AEs and serious AEs (SAEs). Patients were also encouraged to report all AEs at any time during the study period. The Kaplan-Meier method was used to estimate the proportion of patients with any AEs by end of Day 28. Causality assessment was made on all AEs/SAEs using the WHO/UMC (Uppsala Monitoring Centre) causality method. RESULTS: A total of 1103 eligible patients were administered Inj AS, of which 360 patients were in Ghana and 743 in Uganda. The incidence of any AE by the end of follow-up among patients treated with AS was estimated to be 17.9% (197/1103) (95% confidence interval [CI] 15.8-20.3). The median time-to-onset of any AEs was 9 days (interquartile range (IQR) = 4, 14). The top five AEs recorded among patients treated with AS were pyrexia (3.5%), abdominal pain (2.5%), diarrhoea (1.7%), cough (1.5%) and asthenia (1.5%). Most of these top five AEs occurred in the first 14 days following treatment. Regarding the relatedness of these AEs to Inj AS, 78.9% of pyrexia (30/38), 63.0% of pain (17/27), 68.4% of diarrhoea (13/19), 85.5% of cough (14/16) and 75.0% of asthenia (12/16) were assessed as 'possibly' related. There were 17 SAEs including 13 deaths. Two of the deaths are 'possibly' related to Inj AS, as were three non-fatal SAEs: severe abdominal pain, failure of therapy and severe anaemia. CONCLUSION: The incidence of common AEs among patients treated with Inj AS in real-world settings was found to be relatively low. Future studies should consider larger cohorts to document rare AEs as well. CLINICALTRIALS. GOV IDENTIFIER: NCT02817919.

Safety monitoring of a new pentavalent vaccine in the expanded programme on immunisation in Ghana.

BACKGROUND AND OBJECTIVE: Safety monitoring of vaccines used in expanded programmes on immunisation is important in all countries, including those with limited resources. As the rates of target diseases decrease, parents become less accepting of even minor common adverse events. Identification, detection, prevention and appropriate communication of adverse events following immunisation (AEFI) are therefore essential to preserve the integrity of immunisation programmes and protect public health. The objective of this study was to document the occurrence of common minor AEFI associated with a newly introduced pentavalent vaccine for routine immunisation in Ghana's expanded programme on immunisation. METHODS: A prospective descriptive study on AEFI associated with the administration of a pentavalent diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type B (DTP-hepatitis B vaccine/Hib vaccine) vaccine that is part of the Expanded Programme on Immunisation was carried out in four locations in Accra, Ghana. These locations were the nation's premier teaching hospital (the Korle-Bu Teaching Hospital) two urban polyclinics (the Mamprobi and Ussher Town polyclinics) and a community immunisation centre (the Zongo Junction Immunisation Centre).A total of 406 infants were recruited for the study. Upon receipt of signed informed consent from the parents/guardians of the infants, the parents/guardians were supplied with a pink card that functioned as a pseudo-diary for recording AEFI that occurred at home and for measuring and noting the sizes of any injection-site swellings that might occur. It also enabled each participant to obtain free medical care at the Department of Child Health, Korle-Bu Teaching Hospital for the duration of the study (from September 2003 to December 2004) and until the child was 12 months old. Information about the occurrence of AEFI was actively solicited during each visit for immunisation and also at a visit 4 weeks after administration of the last dose of pentavalent vaccine, when participants were asked to report to the respective immunisation centres for the specific purpose of reporting any AEFI which might have occurred in the intervening period. These AEFI were analysed separately from those reported to the dedicated hospital unit at the Department of Child Health, Korle-Bu Teaching Hospital, since the AEFI reported to that unit were all verified and recorded by trained physicians. RESULTS: Of the 406 infants, 368 completed the study, whereas 38 defaulted or were lost to follow-up. There were 104 attendances to report cases of suspected AEFI requiring physician attention at the Department of Child Health, Korle-Bu Teaching Hospital. These attendances were made by 74 patients who reported 190 events; notable among these were cough (26.3% of all AEFI reported to the hospital), fever (17.4%), common cold (12.1%), vomiting (7.4%) and diarrhoea (6.8%). Three of these visits involved AEFI that were classified as 'serious', since they required hospitalisation, but all three were considered to be unlikely to be related to vaccine administration. In addition, actively solicited information on AEFI following immunisation from 921 individual interviews with the parents/guardians of immunised infants during the follow-up visits resulted in reports of 259 events being reported, the most common, according to crude incidence rates, being fever (14.7%), common cold (3.8%), crying (3%) and cough (2.8%). CONCLUSION: The results of this study show agreement with safety studies on vaccines containing identical or similar antigens performed elsewhere and indicate the safety and tolerability of the pentavalent DTP-hepatitis B vaccine/Hib vaccine in Ghanaian children.

Pre-Exposure Prophylaxis for HIV Prevention: Safety Concerns.

Available evidence supports the efficacy of pre-exposure prophylaxis (PrEP) in decreasing the incidence of human immunodeficiency virus (HIV) infection among high-risk individuals, especially when used in combination with other behavioural preventive methods. Safety concerns about PrEP present challenges in the implementation and use of PrEP. The aim of this review is to discuss safety concerns observed in completed clinical trials on the use of PrEP. We performed a literature search on PrEP in PubMed, global advocacy for HIV prevention (Aids Vaccine Advocacy Coalition) database, clinical trials registry " http://www.clinicaltrials.gov " and scholar.google, using combination search terms 'pre-exposure prophylaxis', 'safety concerns in the use of pre-exposure prophylaxis', 'truvada use as PrEP', 'guidelines for PrEP use', 'HIV pre-exposure prophylaxis' and 'tenofovir' to identify clinical trials and literature on PrEP. We present findings associated with safety issues on the use of PrEP based on a review of 11 clinical trials on PrEP with results on safety and efficacy as at April 2016. We also reviewed findings from routine real-life practice reports. The pharmacological intervention for PrEP was tenofovir disoproxil fumarate/emtricitabine in a combined form as Truvada® or tenofovir as a single entity. Both products are efficacious for PrEP and seem to have a good safety profile. Regular monitoring is recommended to prevent long-term toxic effects. The main adverse effects observed with PrEP are gastrointestinal related; basically mild to moderate nausea, vomiting and diarrhea. Other adverse drug effects worth monitoring are liver enzymes, renal function and bone mineral density. PrEP as an intervention to reduce HIV transmission appears to have a safe benefit-risk profile in clinical trials. It is recommended for widespread use but adherence monitoring and real-world safety surveillance are critical in the post-marketing phase to ensure that the benefits observed in clinical trials are maintained in real-world use.

Association Between the Occurrence of Adverse Drug Events and Modification of First-Line Highly Active Antiretroviral Therapy in Ghanaian HIV Patients.

INTRODUCTION: Patients initiated on highly active antiretroviral therapy (HAART) generally remain on medication indefinitely. A modification in the HAART regimen may become necessary because of possible acute or chronic toxicities, concomitant clinical conditions, development of virological failure or the advent of adverse drug events. The study documents adverse drug events of HIV-positive Ghanaian patients with HAART modifications. It also investigates the association between documented adverse drug events and HAART modification using an unmatched case-control study design. METHOD: The study was conducted in the Fevers Unit of the Korle Bu Teaching Hospital and involved patients who attended the HIV Care Clinic between January 2004 and December 2009. Data from 298 modified therapy patients (cases) were compared with 298 continuing therapy patients (controls) who had been on treatment for at least 1 month before the end of study. Controls were sampled from the same database of a cohort of HIV-positive patients on HAART, at the time a case occurred, in terms of treatment initiation ±1 month. Data were obtained from patients' clinical folders and the HIV clinic database linked to the pharmacy database. The nature of the documented adverse drug events of the cases was described and the association between the documented adverse drug events and HAART modification was determined by logistic regression with reported odds ratios (ORs) and their 95 % confidence interval (CI). RESULTS: Among the 298 modified therapy patients sampled in this study, 52.7 % of them had at least one documented adverse drug event. The most documented adverse drug event was anaemia, recorded in 18.5 % of modified therapy patients, all of whom were on a zidovudine-based regimen. The presence of documented adverse drug events was significantly associated with HAART modification [adjusted OR = 2.71 (95 % CI 2.11-3.48), p < 0.001]. CONCLUSION: Among HIV patients on HAART, adverse drug events play a major role in treatment modification. Occurrence of adverse drug events may be used as a predictor for possible therapy modification. We recommend the institution of active pharmacovigilance in HIV treatment programmes as it permits the proper identification and characterisation of drug-related adverse events. This can help develop approaches towards their management and also justify therapy modifications.

Contributions and challenges for worldwide vaccine safety: The Global Advisory Committee on Vaccine Safety at 15 years.

In 1999, the Global Advisory Committee on Vaccine Safety (GACVS) was established by the World Health Organization (WHO) to provide independent scientific advice on issues relating to the safety of vaccines and immunization. Fifteen years onward, we conducted a multi-faceted review to evaluate the impact, reach and challenges facing GACVS, including the role GACVS plays in informing global, regional and WHO member state vaccine policy. The methods included measures of organizational structure, citation impact, themes approached, and a discussion by previous and current members to evaluate past, present and future challenges. Given the increasing range of data sources and the deployment of many new vaccines, the Committee is facing the complex task of identifying the best available evidence for recommendations on vaccine safety. To help meet the increased demand for public transparency in decision making, GACVS-structured methodology for evidence-based decisions is evolving. GACVS also promotes best practices and capacity building for timely and accurate risk assessment; risk communications; outreach to help countries maintain and, if needed, rebuild public trust in vaccines; and advocacy for bridging the major gaps in vaccine safety capacity globally.

Adverse Drug Reaction Reporting in Africa and a Comparison of Individual Case Safety Report Characteristics Between Africa and the Rest of the World: Analyses of Spontaneous Reports in VigiBase®.

INTRODUCTION: Following the start of the World Health Organization (WHO) Programme for International Drug Monitoring (PIDM) by 10 member countries in 1968, it took another 24 years for the first two African countries to join in 1992, by which time the number of member countries in the PIDM had grown to 33. Whilst pharmacovigilance (PV), including the submission of individual case safety reports (ICSR) to VigiBase(®), the WHO global ICSR database, is growing in Africa, no data have been published on the growth of ICSR reporting from Africa and how the features of ICSRs from Africa compare with the rest of the world (RoW). OBJECTIVE: The objective of this paper was to provide an overview of the growth of national PV centres in Africa, the reporting of ICSRs by African countries, and the features of ICSRs from Africa, and to compare ICSRs from Africa with the RoW. METHODS: The search and analysis interface of VigiBase(®)--VigiLyze(®)--was used to characterise ICSRs submitted by African countries and the RoW. The distribution of ICSRs by African countries was listed and characterised by anatomic therapeutic chemical (ATC) code, Medical Dictionary for Regulatory Activities (MedDRA(®)) system organ class (SOC) classification, and patient age and sex. The case-defining features of ICSRs between Africa and the RoW were also compared. RESULTS: The number of African countries in the PIDM increased from 2 in 1992 to 35 at the end of September 2015, and African PIDM members have cumulatively submitted 103,499 ICSRs (0.88 % of global ICSRs) to VigiBase(®). The main class of products in African ICSRs are nucleoside and nucleotide reverse transcriptase inhibitors (14.04 %), non-nucleoside reverse transcriptase inhibitors (9.09 %), antivirals for the treatment of HIV infections (5.50 %), combinations of sulfonamides and trimethoprim (2.98 %) and angiotensin-converting enzyme (ACE) inhibitors (2.42 %). The main product classes implicated in ICSRs from the RoW are tumour necrosis factor-α (TNFα) inhibitors (5.29 %), topical nonsteroidal anti-inflammatory preparations (2.26 %), selective immunosuppressants (2.08 %), selective serotonin reuptake inhibitors (2.04 %) and HMG CoA reductase inhibitors (1.85 %). The main SOCs reported from Africa versus the RoW include skin and subcutaneous tissue disorders (31.14 % vs. 19.58 %), general disorders and administration site conditions (20.91 % vs. 30.49 %) and nervous system disorders (17.48 % vs. 19.13 %). The 18-44 years age group dominated ICSRs from Africa, while the 45-64 years age group dominated the RoW. Identical proportions of females (57 % Africa and the RoW) and males (37 % Africa and the RoW) were represented. CONCLUSIONS: As at the end of September 2015, 35 of 54 African countries were Full Member countries of the PIDM. Although the number of ICSRs from Africa has increased substantially, ICSRs from Africa still make up <1 % of the global total in VigiBase(®). The features of ICSRs from Africa differ to those from the RoW in relation to the classes of products as well as age group of patients affected. The gender of patients represented in these ICSRs are identical.

Outcomes of a Postexposure Prophylaxis Program at the Korle-Bu Teaching Hospital in Ghana: A Retrospective Cohort Study.

The risk for occupational exposure to HIV is a serious public health problem that is well characterized in the developed world, but less so in the developing countries such as Ghana. This study was undertaken to examine the characteristics of occupational exposure to HIV and the utilization of a risk assessment system (RAS)-based postexposure prophylaxis (PEP) among health care workers (HCWs) and health care students (HCSs) in the Korle-Bu Teaching Hospital (KBTH). During the study period (January 2005-December 2010), a total of 260 and 35 exposures were reported by HCWs and HCSs, respectively. Ward attendants reported the highest incidence rate of 6.46 of 100 person-years (P-Y). The incidence of high-risk exposures was 0.33 of 100 P-Y (n = 65); 60.0% occurred during a procedure of disposing of a needle and 24.6% during a cannula insertion. A total of 289 of the 295 individuals were administered PEP, of which 181 (62.6%) completed the 6-month follow-up testing schedule and none sero-converted. This shows that with a good RAS in place, it is possible to deploy an effective PEP program in a typical African teaching hospital like the KBTH in Accra, Ghana.

Experiences and Lessons From Implementing Cohort Event Monitoring Programmes for Antimalarials in Four African Countries: Results of a Questionnaire-Based Survey.

INTRODUCTION: Cohort event monitoring (CEM) is an intensive method of post-marketing surveillance for medicines safety. The method is based on prescription event monitoring, which began in the 1970s, and has since been adapted by WHO for monitoring the safety of medicines used in Public Health Programmes. CEM aims to capture all adverse events that occur in a defined group of patients after starting treatment with a specific medicine during the course of routine clinical practice. OBJECTIVE: The aims of this study were to describe the experiences of National Pharmacovigilance Centres (NCs) that have used CEM to monitor artemisinin-based combination therapy (ACT) for uncomplicated malaria in the African setting, to raise awareness of some of the challenges encountered during implementation and to highlight aspects of the method that require further consideration. METHOD: A questionnaire-based survey was conducted to capture the experiences of NCs that have implemented CEM for active post-marketing surveillance of antimalarial medicines in sub-Saharan Africa. Six NCs were identified as having implemented CEM programmes and were invited to participate in the survey; five NCs indicated willingness to participate and were sent the questionnaire to complete. RESULTS: Four NCs responded to the survey-Ghana, Kenya, Nigeria and Zimbabwe-providing information on the implementation of a total of six CEM programmes. Their experiences indicate that CEM has helped to build pharmacovigilance capacity within the participating NCs and at the monitoring sites, and that healthcare providers (HCPs) are generally willing to participate in implementing the CEM method. All of the programmes took longer than expected to complete: contributing factors included a prolonged enrolment period and unexpectedly slow data entry. All of the programmes exceeded their budget by 11.1-63.2 %. Data management was identified as a challenge for all participating NCs. CONCLUSIONS: The reported experiences of four NCs that have undertaken CEM studies on ACTs indicate that CEM has helped to build pharmacovigilance capacity within NCs and monitoring sites and that HCPs are willing to participate in CEM programmes; however, the method was found to be labour intensive and data management was identified as a challenge. Reducing the workload associated with CEM, particularly in relation to data management, and integrating the method into the routine work of HCPs and NCs should be considered for future implementation.

Profile of adverse events in patients receiving treatment for malaria in urban Ghana: a cohort-event monitoring study.

BACKGROUND: Antimalarial treatment strategies have changed much in the last 15 years, resulting in an increased variety of medicines available. Active pharmacovigilance methods are important for continued safety surveillance of these medicines, particularly in environments in which there is variability in treatments prescribed and limited confirmatory diagnostic capacity as well as limited ability of spontaneous reporting pharmacovigilance systems to generate much needed safety information quickly and efficiently. OBJECTIVE: Our objective was to use the cohort-event monitoring (CEM) technique to gather drug utilization and adverse event data for patients prescribed antimalarial medicines in an outpatient setting. METHODS: The characteristics of a large urban African cohort of outpatients (n = 2,831) receiving antimalarial medications are described. The cohort was actively surveyed over the subsequent week to record adverse events, using follow-up phone calls, paper reports, and/or voluntary return clinic visits. Adverse events reported in the cohort were analysed overall and by clinically relevant age and medication groupings. RESULTS: At least one event was reported in 29.4 % of patients. Adverse events were more likely to be reported in subjects older than 12 years of age, and by patients prescribed an artesunate-amodiaquine combination. A range of adverse events were reported, the most frequent higher level terms being asthenic conditions (10.1 % of total cohort), neurological signs and symptoms (4.5 %), headaches (3.1 %), appetite disorders (2.1 %), and disturbances in consciousness (1.6 %). There were three reports of possible extrapyramidal events (two cases of tremor "hand and back shaking all over" and one case of tongue protrusion), which may appear to be related to combinations including amodiaquine and an artemisinin. CONCLUSION: The CEM methodology is a useful tool for monitoring the safety of widely available and utilized medicines, particularly in an urban environment where spontaneous reporting yields poor results and where the availability of various regimens and high levels of medicine usage can give valuable 'real-life' safety data. The types and frequencies of events reported reflected the types of events expected in patients prescribed antimalarials and nearly all events reported are listed in the summary of product characteristics of the medicines involved.