NR: not reported; PLWH: people living with HIV
Adult active surveillance studies
Nine active surveillance studies contributed adult data (Table 2). All were available as English full-text reports, except one Malian study reported in both a French-language article39 and a French-language thesis38 with English abstracts. An Ethiopian study was reported in two complementary articles49,50. Median quality score was 7/10, ranging from 2/10 to 10/10. Studies were conducted in South Africa (two studies37,47, both high quality), Nigeria (two studies43,52), and in Eritrea48, Ethiopia49,50, Malawi42, Mali38,39, and Uganda41. Study duration ranged from 1 month to 16 months, for a median of 6 months. Six studies were single-centre studies at secondary- / tertiary-level hospitals37-39,42,43,49,50,52, while three were conducted in multiple hospitals41,47,48, including primary-level hospitals in two41,48. Where reported, all studies were conducted in medical wards37-39,41,43,47,49,50,52, additionally including intensive care units in one47. Only one study reported universal sampling of all patients admitted to the study wards47; non-random sampling of admitted patients was described in the remainder. In these studies, large numbers of potential participants were often excluded (35%41, 57%52, 69%49,50, 84%42, and 96%43 in five studies, but only 1%37 and 4%38,39 in two others). Reasons for excluding potential participants included no consent41,48-50,52, missing records37,42,49,50, being too ill to cooperate41,49,50,52, admissions for cancer chemotherapy38,39 or delivery48, readmissions52, no drug exposure49,50, or unclear reasons43.
Most studies37-39,41,47-50,52 used prospective folder review as surveillance methodology, but only four37,41,47,48 reported this to have been conducted by multidisciplinary team. ADRs were mostly defined according to the WHO definition37-39,41,43,48-50,52. Five studies37,41,42,47,49,50 reported a clear two-step method, with causality assessment conducted by a multidisciplinary team other than the surveillance team. Naranjo’s causality assessment method (in 4 studies41,42,48-50) and the WHO-UMC method (in three studies37,47,52) were mostly used. Six studies reported assessing the preventability of ADRs, using Schumock and Thornton criteria in three studies37,41,47 and unreported or other methods in three studies48-50,52.
Apart from summary demographic statistics, the population included in studies’ denominator was generally poorly described. Mean or median age ranged from 36 to 50 years (reported in six studies37-39,41,47,49,50,52), and the proportion of females from 42% to 56% (reported in seven studies37-39,41,43,47,49,50,52). Only two studies reported the proportion of patients included in the denominator that were exposed to drugs before their admission47,49,50. Only two studies described the most common reason for admission, being malaria41 and cardiovascular disease47 respectively. HIV prevalence among patients included in the denominator was only reported in the South African studies, being 32% in the earlier37 and 29% in the later47 study. The proportion of patients in the denominator who were taking ART increased in the interval between these two studies from 5.2%37 to 14%47, and was 11% in the Ethiopian study49,50.
Among the nine active surveillance studies in adult populations, the median [IQR] proportion of admissions attributed to ADRs was 6.4% [4.0% to 8.4%]. Although more studies assessed the preventability of ADRs, only one study, from South Africa, reported the proportion of admissions attributed to preventable ADRs, which was 3.7%47.
Four studies reported the drugs or drug classes implicated in ADRs causing admission to hospital37,42,47,49,50, with striking similarities: antiretroviral agents, antituberculosis therapy, cardiovascular drugs and hypoglycaemic drugs predominated. Common clinical presentations of these ADRs, as reported in five studies37-39,42,47,49,50, mostly related to their hepatotoxic and nephrotoxic effects, and hypoglycaemia. Bleeds from non-steroidal anti-inflammatories and antithrombotic agents were less frequently reported.47,49,50
Four studies reported HIV prevalence among patients who were admitted to hospital for ADRs. This was 38% in both South African studies37,47, 28% in the Ethiopian study49,50, and 3/3 in the Malawian study.42
Paediatric active surveillance studies
Five active surveillance studies contributed paediatric data (Table 3), including two from Nigeria36,40, two from South Africa51,53, and one from Eritrea48. All were available as English full-text articles, with median quality score 5/10, although two studies40,53 scored 10/10. Study duration ranged from 1 month to 36 months. Three studies were single-centre studies at secondary- / tertiary-level hospitals36,40,51 while two were conducted in multiple hospitals48,53, including primary-level hospitals in one48. One study53 surveyed patients admitted to intensive care units in addition to those admitted to paediatric wards. Only one study reported universal sampling of all patients admitted to the study wards36; non-random sampling of admitted patients was described in the remainder. In these studies, unknown numbers of potential participants were excluded for reasons including no consent48,51, missing records40, short duration admissions40,51, admissions for rehydration53, repeat admissions40, elective admissions53, or neonatal admissions48,53.
Four studies reported that multidisciplinary teams conducted the surveillance36,40,48,53. Three studies36,40,48 defined ADRs according to the WHO definition. All studies included an assessment of causality, and four36,40,48,53 included an assessment of preventability, although precise methods varied.
Only one study reported the proportion of patients included in the denominator that were exposed to drugs before their admission53. Infectious diseases were frequently reported as the reason for admission36,40,51,53. The proportion of children in the denominator population who had HIV infection was only reported in the two South African studies51,53.
The proportion of admissions attributed to ADRs ranged from 0.4% to 5.7%, median [IQR] 1.8% [0.6% to 4.7%]. At the low end of the range were the two large Nigerian studies which seemingly included older children, with one study reporting the mean age among all admissions being 6.4 years40. In contrast, the South African studies’ populations were younger (median age 1.4 years51 and 0.9 years53). Hypersensitivity reactions, including erythema multiforme, Stevens Johnson syndrome, urticaria, and rashes were reported as the most common presentations, and antimicrobial medicines were most commonly implicated. Two studies reported the proportion of admissions attributed to preventable ADRs, which were 0.1%40 and 0.5%53 respectively. Only one study, conducted in South Africa, reported HIV prevalence among children admitted for ADRs, being 15%.53