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6 November 2025

Post-Marketing Pharmacovigilance Study of Darunavir in the United Kingdom: An Analysis of Adverse Drug Reactions Reported to the MHRA

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,
and
1
School of Pharmacy, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
2
School of Nursing and Allied Health, Birmingham Newman University, Genners Lane, Bartley Green, Birmingham B32 3NT, UK
*
Author to whom correspondence should be addressed.
Pharmacoepidemiology2025, 4(4), 25;https://doi.org/10.3390/pharma4040025
This article belongs to the Special Issue Pharmacoepidemiology and Pharmacovigilance in the UK
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Abstract

Background/Objectives: Human immunodeficiency virus (HIV) continues to be a global public health concern. Several antiretroviral drugs have been approved for the treatment, post-exposure, and pre-exposure prophylaxis of HIV. Darunavir (DRV) is a protease inhibitor (PI) approved for the management of HIV globally. This study aims to generate safety signals for DRV through data mining and analysis of adverse events (AEs) reported to the United Kingdom (UK) Medicines and Healthcare products Regulatory Agency (MHRA) Yellow Card Scheme. Methods: Disproportionality analysis was conducted using reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN) approaches to identify potential safety signals. Results: The MHRA database contained n = 779 reports (n = 1791 AEs) attributed to DRV. The majority of AEs were reported for males. Positive safety signals were identified at both the system organ class (SOC, n = 5) and preferred term level (PT, n = 95). At SOC level, endocrine disorders emerged as a signal of interest n = 33 cases (ROR: 8.17, 95% CI: 5.78–11.56; PRR:7.96, 95% CI: 5.68–11.15; and IC: 2.85, IC025: 2.51). Among the results, 40 new potential safety signals are not listed on the product labelling in the UK. These include serious AEs such as cerebrovascular accident, brain injury, thrombosis, and pregnancy, puerperium, and perinatal AEs. Conclusions: This study provides additional real-world safety data for DRV in the UK and paves the way for future observational studies to investigate the identified safety signals.

1. Introduction

Human immunodeficiency virus (HIV) continues to be a global public health concern. The World Health Organization (WHO) has estimated global prevalence to be approximately 40.8 million people living with HIV (PLWH) in 2024, the majority (96.7%) of whom are aged ≥15 years old. Furthermore, around 31.6 million PLWH are on antiretroviral therapy (ART) [1]. The benefits of ART are remarkable; it restores immune function and reduces the risk of opportunistic infections [2]. Consequently, it improves the life expectancy and quality of life (QoL) of PLWH [3,4].
Adherence to ART is one of the crucial factors of successful HIV management. However, adherence to medicines decreases as the complexity of the regimen increases, particularly with an increase in daily doses and pill burden [5]. Additionally, AEs associated with ART significantly affect treatment adherence, which may lead to poor clinical outcomes [5]. ART discontinuation is associated with increased risks of viremia, developing drug resistance, and a decline in the cluster of differentiation 4 helper cells (CD4 T cells) [2]. Studies estimate that the discontinuation rate of ART due to AEs is approximately 38–45% [6,7].
Since the discovery of the first anti-HIV drug, zidovudine, in 1987, several other drug classes have been discovered. These include nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), e.g., lamivudine and tenofovir, non-nucleoside reverse transcriptase inhibitors (NNRTIs), e.g., efavirenz and nevirapine, protease inhibitors (PIs), e.g., darunavir and atazanavir, integrase strand inhibitors (INSTIs), e.g., dolutegravir and raltegravir, entry inhibitors, e.g., maraviroc and enfuvirtide, and pharmacokinetic enhancers (PEs), e.g., ritonavir and cobicistat [8,9,10,11]. These drugs are used in combination antiretroviral therapy (cART). Typically, cART consists of two NRTIs drugs and one drug from one of the following classes: an INSTI, NNRTI, boosted PI, or an entry inhibitor [12].
Darunavir (DRV) is a second-generation PI that was approved by the European Medicines Agency (EMA) in 2008 for the treatment of HIV in ART treatment-experienced adults, including those with HIV-1 resistance to more than one PI [13]. DRV is co-administered with either cobicistat or a low dose of ritonavir as a pharmacokinetic enhancer in combination with other antiretroviral drugs [14].
PIs competitively inhibits the activity of HIV-1 proteases, an essential enzyme during the HIV-1 cell cycle. HIV-1 protease is a homodimeric aspartyl protease that cleaves the precursor Gag and Gag-Pol polypeptides to generate structural proteins and other HIV-1 key enzymes such as integrase, protease, RNase H, and reverse transcriptase. The Gag and Gag-Pol viral polyproteins are responsible for viral assembly and ultimately the release of mature virions from the host cells [15,16].
Post-authorisation observational studies have demonstrated that DRV-based therapies are generally well tolerated [17,18]. DRV has a favourable safety profile; however, several AEs have been reported in both clinical trials and real-world studies, including hepatic disorders, cardiovascular disease, metabolic disorders, gastrointestinal disorders, pancreatitis, sexual dysfunction, and lipodystrophy [19,20,21,22]. Recently, there have been mixed safety findings regarding the cardiovascular risk associated with DRV-based therapies. A multi-centre study revealed evidence of approximately 50% increased risk of cardiovascular (CVD) risks associated with 5 years cumulative exposure to darunavir boosted with ritonavir (DRV/r) compared to those not exposed [23]. In contrast, Costagliola et al. reported no increased risk of CVD AEs associated with DRV [24]. Similarly, an Antinori et al. found no evidence of CVD AEs association [25]. Additionally, a 2024 review reported potential adverse pregnancy outcomes with the use of PIs (including DRV), which include intrauterine growth restriction, preterm birth, small-for-gestational-age infants, and early-onset severe preeclampsia [26].
Despite these risks versus benefits, DRV remains an important component of cART. A recent study has demonstrated that DRV/r plus dolutegravir (DTG) is a highly potent second-line strategy combination compared to the (DTG + Tenofovir + Lamivudine/Emtricitabine) (DTG + TDF/XTC) combination. This supports the WHO recommendation of DRV/r as an alternative second-line ART regimen for adults, adolescents, children, and infants [27]. Furthermore, in the UK, DRV is recommended as one of the two-drug regimens for treatment switches for virally suppressed patients or as maintenance therapy [3]. Given all these factors, DRV plays a critical role in HIV management, and as such, it is timely to continuously monitor its safety profile within the UK population. Previously, a pharmacovigilance study employing the United States of America (USA) Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database revealed several positive safety signals for DRV and its boosted agents including progressive acute pancreatitis, extraocular muscle paralysis, exfoliative dermatitis, stillbirth, premature birth and premature rupture of membranes [28].
To contribute to these efforts, a retrospective pharmacovigilance study was conducted to provide insights into the long-term post-marketing safety of DRV in the UK population. This study provided additional AE signal information on the safety profile of DRV in the UK, which involves diversity in terms of population demographics, ethnicities, prescribing patterns, and healthcare practices that differ from the USA.
This study interpreted AEs reported to the Medicines and Healthcare products Regulatory Agency (MHRA) by healthcare professionals, patients, carers, and pharmaceutical companies. The data underpinning this study are publicly available through the interactive Drug Analysis Profiles (iDAPs) on the Yellow Card Scheme, which provides essential UK-specific information for conducting this pharmacovigilance study. The aims of the study were to investigate potential AE signals associated with DRV from launch in 2006 to 19 May 2024 (last collection datapoint timestamp for this study).

2. Results

From 1963 to 19 May 2024, there were n = 1,345,712 reports associated with n = 2499 unique drugs within the complete MHRA database. Among these, n = 779 reports (n = 1791 AEs) were suspected to be associated with DRV. The clinical characteristics of all AEs are described in Table 1. Males (59.56%) accounted for a greater number of AEs compared to females (34.40%), and 6.03% were classified as unknown gender. Regarding age groups, the majority (39.15%) of reports were classified as unknown age of the patient. This was followed by the 40–49 age group, which accounted for 18.23% of all AEs associated with DRV. The majority of the reports were serious (74.84%), followed by nonserious (16.17%), and 8.99% were fatal. AE reports were mainly reported by healthcare professionals (98.07% of reports received).
Table 1. Characteristics of reports associated with darunavir (DRV).

2.1. Serious vs. Non-Serious Adverse Events (AEs)

A chi-squared test of independence was used to assess the relationship between the seriousness of cases and gender. There was a statistical association between gender and the seriousness of the AEs. Males had a significantly higher risk of serious AEs compared to females (OR [95% CI] = 1.76 [1.31–2.36], p < 0.05) (Table 2).
Table 2. Comparison of patient gender and age group between serious and non-serious adverse events (AEs).

2.2. Signal Detection at the System Organ Class (SOC) Level

Suspected AEs were analysed at the SOC level as per the Medical Dictionary for Regulatory Activities (MedDRA, version 27.0). Table 3 and Supplementary Table S1 present five SOCs identified with positive safety signals. These include (i) congenital, familial, and genetic disorders, (ii) endocrine disorders, (iii) hepatobiliary disorders, (iv) pregnancy, puerperium, and perinatal conditions, and (v) renal and urinary disorders. Endocrine disorders demonstrated the strongest signal n = 33 cases (ROR: 8.17, 95% CI: 5.78–11.56; PRR:7.96, 95% CI: 5.68–11.15; and IC: 2.85, IC025: 2.51).
Table 3. Signal strength of darunavir (DRV) adverse events (AEs) at the system organ class (SOC) level.

2.3. Males Versus Females for Selected System Organ Classes (SOCS)

Gender influence on the reporting rate of AEs was investigated for SOCs that showed positive signals at the SOC level. There was no statistical association between gender and hepatobiliary disorders and endocrine disorders (OR [95% CI] = 0.73 [0.39–1.34], p = 0.299) and (OR [95% CI] = 0.58 [0.24–1.37], p = 0.198), respectively. However, a statistically significant association was observed between gender and renal and urinary disorders (OR [95% CI] = 2.98 [1.54–6.36], p < 0.05), gender and congenital, familial, and genetic disorders (OR [95% CI] = 0.18 [0.07–0.39], p < 0.05) and pregnancy, puerperium, and perinatal conditions (OR [95% CI] = 0.12 [0.05–0.24], p < 0.05). Renal and urinary disorders were reported more frequently for males compared to females, while females reported more pregnancy, puerperium, and perinatal (PPP) conditions and congenital, familial, and genetic disorders, as was expected based on biology. The association of PPP conditions with males was due to the sex of the child via transplacental exposure. All male pregnancy, puerperium, and perinatal condition AEs were reported for 7 children aged 0–9 years as a result of perinatal exposure (Table 4).
Table 4. Comparison of patient gender and selected system organ classes (SOCs) associated with positive AE signals for DRV.

2.4. Signal Detection at the Preferred Term (PT) Level

Overall, our analysis at the preferred term level (PT) identified n = 611 PTs that were reported for DRV, with 95 positive safety signals determined by criteria thresholds in Section 5.2. Supplementary Table S2 provides a list of all n = 95 positive safety signals. Table 5 presents 44 positive safety signals at the PT level that had a minimum of n = 5 AEs associated with the signal.
Table 5. Signal strength of darunavir adverse events (AEs) at the preferred term (PT) level.

3. Discussion

Randomized clinical trials (RCTs) provide critical safety data during the drug discovery process and the subsequent approval of medicinal products [29]. In addition, most clinical treatment guidelines are based on data sourced from RCTs. However, RCTs have shortfalls, as often the data do not provide a comprehensive safety profile of medical products owing to the limited duration of RCTs, small sample size, and exclusion of high-risk population groups [30,31,32]. Therefore, post-marketing surveillance and pharmacovigilance studies are essential to provide real-world safety data. In this study, we conducted a retrospective longitudinal analysis of AEs associated with DRV that were reported to the MHRA from 2006 until 19 May 2024.
This study revealed that AEs are more likely to be reported in males (59.56%) compared to females (34.40%). Contrary to this, two studies analysing the WHO-ADR database, VigiBase™, in the general patient population observed that approximately 60.00% of all reported AEs were for females [33,34]. Similarly, Brabete et al. demonstrated that more females reported AEs than males in a systematic review of pharmacovigilance studies [35]. In contrast, another pharmacovigilance study evaluating the safety of tenofovir alafenamide reported that 56.60% of males reported AEs versus 39.70% for females [36]. The study utilised the HIV patient data in the USA, where the HIV prevalence rate is higher among males (approximately 77%) [37]. This is similar to the UK, where 72.10% of PLWH are males [38]. These figures need to be seen in the context of HIV and cART Rx rates where more males report ART-related AEs because they are significantly more likely to be prescribed HIV medications compared to females. Furthermore, the current study revealed that males were statistically more likely to experience serious AEs associated with DRV than females. This is consistent with findings from a scoping review of pharmacovigilance studies across the USA, Canada, the UK, Australia, and countries from the European Union (EU), which examined gender-based differences in AEs reporting. The study identified that women disproportionately reported more AEs, while men reported more serious AEs [35]. In addition, women are often proactive with health issues and are most likely to connect the onset of the AE with the medication and will seek medical care more quickly before the AE worsens [39].
The current study identified 5 positive safety signals at the SOC level for DRV in the UK. Among these are congenital, familial, and genetic disorders, endocrine disorders, hepatobiliary disorders, pregnancy, puerperium, and perinatal conditions, and renal and urinary disorders. With endocrine disorders showing the strongest safety signal. This is consistent with findings from the pharmacovigilance study of DRV and its boosted agent conducted in the US [28]. At the PT level, our study confirmed several AEs previously described by Tian et al. However, the current study identified additional safety signals, including gout, abnormal weight, nephrolithiasis, cerebrovascular accident, neurological symptoms, brain injury, thrombosis, cognitive disorder, amnesia, abnormal dreams, completed suicide, hallucination, dysphagia, and drug reaction with eosinophilia and systemic symptoms (DRESS). With regard to pregnancy AEs, our analysis identified similar AEs and two novel safety signals—foetal distress syndrome and gestational diabetes. Together, the current study provides confirmatory external validation of previously identified AEs and has identified novel potential AEs from the UK population.
Our analysis has revealed several positive signals that are already listed in the DRV SmPC [14]. These include several hepatic system signals: drug-induced liver injury, hepatitis acute hepatitis, hepatotoxicity, increased alanine aminotransferase, increased blood bilirubin, and increased hepatic enzymes. Investigation signals: increased blood glucose, decreased weight, abnormal weight gain, hyperlipidaemia, and increased blood triglycerides. In addition, six signals relating to skin and subcutaneous tissue disorders were identified: nail discolouration, maculo-papular rash, skin striae, skin ulcer, acquired lipodystrophy and lipohypertrophy. With regard to renal and urological disorders, our analysis identified renal impairment, renal disorder, nephrolithiasis, decreased estimated glomerular filtration rate (eGFR), and proteinuria.
This analysis identified known endocrine AEs, including secondary adrenocortical insufficiency, Cushing’s syndrome, adrenal insufficiency, and Cushingoid, which are listed in the DRV SmPC in the UK. However, it is important to note that DRV/r and darunavir boosted with cobicistat (DRV/c) share the same SmPC and that endocrine disorders AEs are only listed for DRV/r [14]. Ritonavir is implicated in several drug–drug interactions (DDIs). It is a substrate of several key metabolically important enzymes, including cytochrome P450 (CYP450). Ritonavir is an inhibitor of CYP3A4, CYP2D6, and P-glycoprotein (Pgp). Further, it is an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and UDP-glucuronosyltransferase (UGT), increasing the risk of AEs [40]. Co-administration of CYP3A-metabolised corticosteroids and DRV/r or DRV/c is not recommended unless the potential benefits outweigh the risk for a specific patient. However, if such treatment is clinically justified, potential systemic corticosteroid effects should be monitored [14].

3.1. Novel Positive Safety Signals

3.1.1. Cerebrovascular Adverse Events (AEs)

The current study has revealed new potential safety signals associated with DRV: cerebrovascular accident and thrombosis, neither of which is listed in the SmPC [14]. Previous studies have established a link between ischemic stroke incidence and HIV infection [41]. Coagulopathies [42], opportunistic infections [42], cardioembolism [43], HIV-associated vasculopathy [44], metabolic abnormalities [45], atherosclerosis, and ART has been described as potential contributing factors [43,46]. While ART has improved the QoL of PLWH, they are faced with other comorbidities that may be directly or indirectly related to ART, such as stroke [41]. AEs associated with ART, including metabolic changes and lipodystrophy, are recognised risk factors of cardiovascular and cerebrovascular diseases [23]. The association between PIs and the risk of myocardial infarction (MI) and stroke has been noted, owing to several factors including metabolic changes [47]. This study has identified cerebrovascular events and thrombosis as novel safety signals, but it is worth noting that stroke is multifactorial in nature. Therefore, observational studies adjusting for risk factors should be conducted to assess these novel signals. In addition, we observed other nervous system-related safety signals, including brain injury, central nervous system lesion, cognitive disorder, neurological symptoms, and amnesia, the latter being the only one currently listed in the SmPC [14]. HIV infection is known to cause HIV-associated neurocognitive disorder (HAND), which encompasses a spectrum of neurocognitive deficits [48,49]. Therefore, some of the reported events may not be related to DRV; thus, further investigation is needed.

3.1.2. Congenital Anomalies and Pregnancy Adverse Events (AEs)

We identified abortion, spontaneous abortion, foetal death, foetal distress syndrome, foetal growth restriction, gestational diabetes, low birth weight baby, premature baby, premature delivery, and premature labour as positive safety signals in this study. In 2022, it was estimated that 1.2 million HIV positive women were pregnant globally, among these, 85.0% had access to ART [50]. The importance of ART during pregnancy is well recognised, particularly for two main reasons: (i) to prevent disease progression during pregnancy and (ii) to prevent vertical transmission to the foetus [51]. Guidelines recommend the use of cART, including PI, during pregnancy, taking into consideration safety and efficacy. In the US, DRV/r is preferred for pregnant women who have previously used long-acting injectable cabotegravir (CAB-LA) for pre-exposure prophylaxis [52]. Similarly, in the UK, DRV/r (600/100 mg) twice daily is one of the preferred anchor agents for HIV-infected pregnant women [53]. Low therapeutic levels due to pharmacokinetic (PK) changes during pregnancy limit the use of DRV/c [54].
Mandelbrot et al. recently evaluated the effects of switching pregnant women from standard triple therapy to DRV/r monotherapy. Amongst those switched, the study reported the following incidence rates: pre-term deliveries (9.5%), pre-eclampsia (5.6%), diabetes mellitus (16.9%), cholestasis (grade ≥3) (2.2%), low birthweight (9.5%), small for gestational age (8.3%), and miscarriages (4.5%) [55]. In addition, the study reported birth defect rates of 3.6% [55], which is comparable to 3.7% in the US antiretroviral pregnancy registry for women who used DRV during pregnancy [56]. In addition, another study, which examined data from the UK/Ireland National Study of HIV in Pregnancy and Childhood, reported a preterm delivery rate of 10.4% for women on ARTs, and higher rates in women using LPVr-based regimens compared to those taking other PI/r or NNRTI-based regimens. Furthermore, the study identified other contributing factors, such as women who conceived while on ART, those with a low CD4 cell count below 350 cells/μL [57]. Our analysis identified exomphalos and spina bifida as positive signals for congenital anomalies. Mandelbrot et al. reported birth defect rates of 1.2% for each of the following: congenital diaphragmatic hernia, pulmonary sequestration, hydronephrosis, and skin haemangioma in women exposed to DRV as a monotherapy [55]. Preclinical studies demonstrated no teratogenicity of DRV alone in rats and rabbits or in combination with ritonavir in mice [14]. It is challenging to take into consideration other factors such as CD4 cell count, concomitant medications, and social, economic, education, and environmental factors that could affect pregnancy outcomes. Therefore, there is a need for controlled studies to further evaluate the use of DRV in pregnancy.

4. Limitations

Spontaneous reporting systems (SRS) are essential for monitoring the safety of medical products once they are authorised for use by the public. SRS provides heterogeneous data that allows a comprehensive assessment of medicines throughout their life cycle. The current study used data submitted by HCPs, patients, caregivers, and pharmaceutical companies reported to the MHRA through the Yellow Card Scheme [58]. It is well known that SRSs have several shortfalls, including under-reporting, biased reporting, and incomplete reports. In addition, other concerns with SRSs include a lack of denominator or population exposure for estimating incidence, and multiple confounding factors are not accounted for. Consequently, this affects the reliability of the conclusions made from studies that utilise SRS data [59,60].
The current study employed PRR and ROR as frequentist disproportionality methods, along with an IC Bayesian approach for signal detection. However, the numerical output of disproportionality analysis indicates the reporting frequencies (observed versus expected ratios) rather than actual estimates of the occurrence of an AE in a specific population [61]. Therefore, the statistical output does not confirm causality. DRV is boosted by either cobicistat or ritonavir, which individually could cause AEs, however data for DRV as the single active constituent suspected of the AE was used. The Yellow Card Scheme iDAPs database utilised could not be stratified to assess AEs for each specific booster and DRV independently.

5. Materials and Methods

5.1. Data Sources and Processing

This retrospective pharmacovigilance study was conducted in accordance with READUS-PV (REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance) guidelines [62]. The study used data extracted from the MHRA Yellow Card scheme database, which is publicly available through interactive Drug Analysis Profiles (iDAPs). The MHRA Yellow Card scheme database collects spontaneous AE reports for medicines, vaccines, and medical devices from across the UK. These are reported by healthcare professionals, patients themselves, carers, as well as the pharmaceutical industry [63].
In the MHRA database, AEs are coded by Medical Dictionary for Regulatory Activities (MedDRA, version 27.0). The highest level of MedDRA is System Organ Class (SOC), and for this study, AEs analysed were at the SOC and preferred term (PT) level. CSV files for all drugs were downloaded from iDAPs. The drug, event, and case CSV files for each drug were merged. Then the CSV files for all drugs were combined to generate a masterfile for all drugs. The CSV masterfile had the following columns: sequential number identifying a single AE report, sex, age (10-year bands), year received by MHRA, sender type (direct or indirect), reporter (healthcare professional or carer/patient), seriousness (non-serious, serious, or fatal), and route of administration. The dataset included all suspected adverse events (AEs) associated with DRV, where it is reported as a single active constituent, from the time the first report was made (2006) until 19th May 2024 (date of download of raw data used in this study).
In the UK, DRV is available in formulations that are either boosted with cobicistat or ritonavir. However, the MHRA database does not specify which pharmacokinetic enhancer was used to boost DRV. Therefore, all AEs were analysed collectively, regardless of the pharmacokinetic enhancer used.

5.2. Data Mining and Statistical Analysis

Disproportionality analysis was conducted to assess whether DRV was significantly associated with reported AEs at the PT and SOC levels. The signals of disproportionate reporting (SDRs) were generated by employing the reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN), these methods were based on a two-by-two contingency table (Table 6). A positive safety signal was detected when the thresholds of all 3 methods were met (Table 7). The higher ROR, PRR, and BCPNN values indicate stronger signals.
Table 6. Two-by-two contingency table.
Table 7. Algorithms used for signal detection.
Descriptive analyses were conducted to summarise the clinical characteristics of the suspected AEs. The MHRA classifies cases into fatal, serious, and non-serious. A chi-squared test of independence was used to determine the relationship between the seriousness of cases (serious vs. non-serious) and gender (male and female). Furthermore, to examine the relationship between gender and the distribution of AEs across SOCs, separate chi-squared tests of independence were conducted for each SOC. A significance level of p-value < 0.05 was used to determine statistical significance. All analysis was performed using RStudio, 2024.12.0 Build 467, © 2009–2024 Posit Software, PBC.

5.3. Summary of Product Characteristics (SmPC) Comparison to AE Signals Identified with DRV

Cross-referencing between identified positive signals at the preferred term (PT) level and listed side effects in the DRV SmPC (for both pharmacokinetic enhancers) was performed to determine novelty. Where the positive signals are absent in the DRV SmPC, an additional review was checked in the ritonavir SmPC. Approved labels used were extracted from the MHRA [14,64] websites.

6. Conclusions

This study comprehensively analysed AEs associated with DRV, which were reported to the MHRA through the Yellow Card Scheme. The study identified known/expected AEs associated with DRV, which are listed in the SmPC. Furthermore, this study identified new potential safety signals, including cerebrovascular accident, brain injury, thrombosis, abnormal weight, increased weight, gout, and dysphagia, which are not listed in the SmPC and may reflect emerging safety concerns. Additionally, there is a need for continuous monitoring of metabolic parameters in patients taking DRV, as these metabolic changes are risk factors for cardiovascular diseases and cerebrovascular accidents. In addition, several safety signals relating to pregnancy, puerperium, and perinatal conditions have been noted. Overall, this study provides additional real-world safety of DRV outside a clinical trial setting in the UK population. However, it is important to interpret these findings with caution, as they are statistical associations and do not prove causality [62]. Nevertheless, new potential safety signals require further investigation with high-quality real-world studies to assess the safety of DRV systematically and to establish if there is a causal relationship between DRV and identified AEs.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/pharma4040025/s1, Table S1: Signal strength of darunavir adverse events (AEs) at the SOC level; Table S2: Signal strength of all adverse events (AEs) meeting the criteria for a positive safety signal at the PT level.

Author Contributions

Conceptualization, P.P. and A.M.J.; methodology, P.P.; validation, P.P., V.S., V.C. and A.M.J.; formal analysis, P.P.; investigation, P.P.; resources, A.M.J.; data curation, P.P.; writing—original draft preparation, P.P.; writing—review and editing, P.P., V.S., V.C. and A.M.J.; visualization, P.P.; supervision, A.M.J., V.C., V.S.; project administration, A.M.J.; funding acquisition, P.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research was conducted as part of a PhD program supported by the Government of Botswana.

Institutional Review Board Statement

Ethics approval was granted through the University of Birmingham’s Research Ethics Committee (ERN_4319-May2025) on 1 May 2025.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author(s).

Acknowledgments

The authors thank the MHRA for providing open access to ADRs reported in the UK.

Conflicts of Interest

The authors declare no conflicts of interest.

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Exploratory Signal Detection of Maternal and Perinatal Adverse ART Drug Events in EudraVigilance: Insights from Network and Cluster Analyses
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