Results

Descriptive Analysis

A total of 15,942,925 reports from the first quarter of 2004 to the fourth quarter of 2022 were screened from the FAERS database, and a total of 8,420, 11,625, 3,115 and 344 reports related to ACV, VACV, GCV, and FCVADEs were obtained, respectively. In addition to GCV, the gender of patients in the report is mainly female, with ACV accounting for 47.16%, VACV accounting for 57.99%, and FCV accounting for 60.17%. The patient’s age is mainly outside the range of 15-60 years old (ACV 77.61%, VACV 82.35%, GCV 77.98%, FCV 88.08%). The reporting personnel are mainly medical personnel and consumers themselves. The main route of administration, excluding unknown and lost routes, is oral administration (ACV 29.19%, VACV 74.87%, GCV 22.57%, FCV 63.37%). The reporting countries are mainly developed countries (Table 2).
Table 3 lists the high-frequency PT related to the use of ACV, VACV, GCV, and FCV in the ADEs report (top 10). Among the top 10 indications for ACV, VACV, and FCV, herpes zoster, herpes simplex, oral herpes, herpes virus infection prevention, antiviral prevention, genital herpes, and other confirmed indications were all present. Encephalitis (2.11%) is a separate indication in ACV. Facial nerve paralysis (1.16%) and necrotizing retinitis (0.87%) were the two indications of FCV. High frequency indications in GCV include cytomegalovirus infection (24.11%), cytomegalovirus viremia (4.33%), cytomegalovirus chorioretinitis (3.88%), congenital cytomegalovirus infection (3.05%), and cytomegalovirus colitis (2.09%).

Disproportionality analysis

The ADEs signals of ACV, VACV, GCV and FCV were screened, and the total number of PT reports with signals was finally divided into 18,901, 6,299, 371 and 24,606 cases by ROR, PPR and BCPNN. On this basis, taking ROR method as an example (ROR and PPR methods have good consistency in specificity and signal detection ability, and the sensitivity of ROR method is higher), PT sorting and SOC classification are performed according to the top 10 reports (a value) of this ADEs, and the results are shown in Table 4. The high-frequency PT of ACV (Drug ineffective N=917,ROR=1.28; Pyrexia N=318,ROR=1.64; Condition aggravated N=252,ROR=1.69; Drug resistance N=213,ROR=16.15)、VACV(Drug ineffective N=1505,ROR=1.88)、GCV (Drug resistance N=317,ROR=84.25)、FCV(Drug ineffective N=40,ROR=1.76;Feeling abnormal N=11,ROR=2.41;Malaise N=15,ROR1.85) affects general diseases in the SOC system and occurs simultaneously in the four lovir drugs mentioned above, indicating that the SOC system has the highest cumulative number of reported ADEs. High frequency PT in ACV (N=957, ROR=8.88), FCV (N=16, ROR=4.55) and VACV (N=857, ROR=6.95) simultaneously involved kidney and urinary system diseases, and the PT was acute kidney injury.The high-frequency PT in ACV (N=324 ROR=3.51), FCV (N=11, ROR=3.72), and VACV (N=451, ROR=4.31) simultaneously affects mental disorders, and these PTs are all in a Confusional state. Nervous system disease (ACV: Neurotoxicity N=394,ROR=47.47 FCV: Headache N=23,ROR=2.05;Altered state of consciousness N=18,ROR=50.40; Dizziness N=18,ROR=2.01 VACV: Dizziness N=608,ROR=1.92; Altered state of consciousness N=569,ROR=46.43; Headache N=563,ROR=1.41; Dysarthria N=427,ROR=17.54), Skin and subculture tissue disorders (ACV: Rash N=330 ,ROR=1.33; Pruritus N=244,ROR1.21; Erythema N=213 ROR=1.79 FCV: Pruritus N=13,ROR=2.03 VACV: Rash N=473,ROR=1.68) are simultaneously involved in high-frequency PT of ACV, FCV and VACV. The SOC of high-frequency PT alone affecting GCV is: injury, poisoning, and surgical complications (Off label use N=394, ROR=3.59; Product use issue N=107, ROR=3.76), infection and invasion (Cytomegalovirus infection N=392, ROR=157.11; Cytomegalovirus viremia N=146, ROR=262.86; Pathogen resistance N=134, ROR=100.87) Disorders of the blood and lymphatic system (Neutropenia N=255, ROR=12.76; Leukopenia N=166, ROR=20.82; Thrombocytopenia N=129, ROR=7.26; Pancytopenia N=124, ROR=14.04 (11.76-16.77); The SOC that individually affects FCV is: heart disease (Palpitations N=10 ROR=4.75); The SOC that affects VACV alone is gastrointestinal disease (Nausea N=690, ROR=1.39; Vomiting N=466, ROR=1.59).
Then, PT ranking was performed based on the top 10 bits of signal strength ROR (95% CI) for the three algorithms that simultaneously satisfy the ROR, PPR, and BCPNN methods, in order to identify PT with high correlation (i.e. strong signal) ( Table 5).Among them, only ACV is affected by PT, which affects Neoplams benignant, malignant, and unspecified (including cycles and polymers) (Cerebellar haemangioma N=3,ROR=246.03); GCV refers to metabolic and nutritional disorders(Cell-mediated cytotoxicity N=255,ROR=740.01), gastrointestinal dysfunction (Oesophagopleural fistula N=146,ROR=568.21, pregnancy, postpartum, and perinatal conditions(Leukopenia neonatal N=129,ROR=357.40); FCV refers to skin and subcutaneous tissue diseases(Cutaneous vasculitis N=8,ROR=104.81), as well as heart diseases(Bundle branch block left N=3,ROR=35.83); The condition that affects psychiatric disorders (Cotard’s syndrome N=16,ROR=344.43;Imperception N=4, ROR=196.26) is VACV. The corresponding PT names and ROR are shown in Tables 4 and 5. Cytomegalo viremia (N=146, ROR=262.86) is present in both high-frequency ADEs of GCV and its strongly correlated ADEs. Changes in consciousness state (N=18, ROR=50.40) occur both in high-frequency ADEs of FCV and in its strongly correlated ADEs.

SOC system distribution

According to MedDRA’s SOC classification and sorting of all signal PTs, there are 11, 9, 6, and 11 SOC systems with signals for ACV, GCV, FCV, and VACV, covering a total of 14 SOC systems. ADEs of the four ”lovir” families can be involved in two SOC systems: congenital, familial and hereditary diseases, kidney and urinary system diseases; The cumulative number of ADEs involved in the SOC system of nervous system disease is the largest, but GCV drug ADEs do not involve this system; The only drugs that affect the SOC system (N=1049, ROR=1.08) for injuries, poisoning, and surgical complications are GCV; The only drugs that affect the SOC system (N=218, ROR=1.26) during pregnancy, postpartum, and perinatal periods are VACV (Table 6, Figure 1).
Discussion
According to Grand View Research, the global antiviral drug market size in 2018 was approximately $56.4 billion, with a domestic market value of approximately $20 billion. The main type of anti-herpesvirus drugs is ”lovir” nucleoside analogues. In recent years, the overall market size of hospital anti herpesvirus drugs has remained stable, with a corresponding market size of approximately 2 billion yuan for drugs on sale. The widespread use of antiviral drugs such as ”lovir” DNA polymerase suggests that it is necessary to refine their usage rules and develop necessary alternative strategies to provide protection against herpes virus infection or remove latent viruses from infected host cells.
Tables 4 and 5 respectively reflect the cross or parallel SOC involvement in ADEs of ACV, GCV, FCV, and VACV in terms of high incidence and strong correlation. The SOC system, which involves damage, poisoning and surgical complications, infection and invasion, as well as blood and lymphatic system disorders, only occurs in the top 10 ADEs with an incidence rate after taking GCV. Its toxicity can cause bone marrow suppression, namely neutropenia, thrombocytopenia, and leukopenia, which can lead to dose changes or cessation of treatment [25-28]. CMV is a major complication of immunocompromised patients, especially in hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT) patients [29]. GCV is the main treatment method for preventing and treating CMV in SOT recipients [30]. However, cytomegalovirus infection and cytomegalovirus emia exhibit high incidence in the real world after taking GCV, indicating that GCV may also bring more serious results during the treatment process. But we cannot elucidate the causal relationship between them, and can only prompt doctors to continuously monitor the patient’s condition during the medication process. Existing data show that the oral treatment of valganciclovir is not inferior to the intravenous treatment of GCV, and its bioavailability is about 60%, almost 10 times that of oral GCV [29]. However, this article does not evaluate the safety of Valganciclovir in the prevention and treatment of CMV in SOT recipients. ADEs exhibit a high incidence of cardiovascular system involvement in the real world, only after taking FCV, and there are currently no reports on their adverse reactions to the cardiovascular system. It is strongly suggested that patients with or at risk of cardiovascular disease should carefully choose FCV and switch to reasonable alternative drugs. ADEs involving gastrointestinal diseases are most common in VACV, which is consistent with current reports of side effects of this drug [31].
Among the top 10 ADEs with strong correlation, ACV was the only one involved in the SOC system of benign, malignant and unknown tumors (including cysts and polyps). The one associated with PT was Cerebellar haemangioma, although it has not been reported definitively with ACV. However, current studies suggest that ACV may be a potential therapeutic supplement for glioblastoma and the mechanism of ACV administration on NCI-H1975 non-small cell lung cancer: mitochondria may be the initial target and/or site of ACV cytotoxicity in cancer cells [32, 33]. Meanwhile, we found one case of ACV associated with glioma and one case of ACV associated with non-small cell carcinoma reported in FAERS. GCV involves metabolic and nutritional disorders, gastrointestinal dysfunction [34] and pregnancy, puerperium and perinatal conditions; FCV involved skin and subcutaneous tissue diseases and heart diseases. VACV is involved in mental disorders [35].The top 10 PT in ACV, GCV and VACV are also involved in the following SOC systems: kidney and urinary system diseases, nervous system diseases, skin and subcutaneous tissue diseases, and psychiatric diseases. At this time, FCV can be used as an alternative drug for HHV-infected patients with these primary diseases.
SOC system general diseases and administration site conditions after taking ACV; Infection and disturbance after taking GCV; General diseases and administration site conditions, nervous system disease, heart diseases, skin and subcutaneous tissue diseases after taking FCV; After taking VACV, mental disease, nervous system disease, general disease and administration site conditions not only express a high incidence rate, but also express a strong correlation. These signals strongly suggest that herpes virus infected patients with corresponding primary diseases should carefully choose corresponding drugs and use other alternative drugs.
Of course, this study also has limitations. Firstly, due to the spontaneity of FAERS reporting, there are some inherent limitations that result in poor data quality, including missing information, incorrect and misclassified information, over reporting, underreporting, and selective reporting. Secondly, FAERS is limited by its nature and cannot draw precise conclusions about the prevalence, incidence, and causal relationship of adverse drug reactions, and there may be significant deviations in reporting based on national concerns or regional awareness [36]. Third, the lack of denominators for drug users limits our ability to estimate the true incidence rate of specific ADEs [24]. However, despite these limitations, data mining in FAERS database can still be regarded as Exploratory research to detect signals of unknown or unexpected ADEs, rather than verification or hypothesis testing of any causal relationship. The safety signals identified from FAERS data should be further investigated in clinical practice [37, 38].