Since the outbreak of COVID-19, there have been more than 5204,000 confirmed cases globally, and 337,687 people have lost their lives[1]. Thousands more are fighting for their lives in hospitals. The World Health Organization (WHO) has characterized COVID-19 as a pandemic. All countries activated and scaled up their emergency response mechanisms, and a great deal of effort has been made to identify effective drugs against the virus. Some PIs, such as lopinavir/ritonavir and darunavir/cobicistat, have been tested in clinical trials in China. This study focused on the occurrence, timing, and prognosis of AP following the use of various PI regimens in real-world practice based on the FAERS pharmacovigilance database. First using disproportionality analysis and Bayesian analysis as a rapid and effective signal detection method to perform the largest-to-date postmarketing surveillance of these PIs, we attempted to provide valuable and timely signals for clinical evaluation to minimize the potential harm induced by AP in the treatment of COVID-19. The study showed that 12 out of the 15 studied PIs, including lopinavir/ritonavir, darunavir, and nelfinavir, which are potential therapeutics for COVID-19, were associated with AP-related adverse events.
Despite the potential benefits it provides to COVID-19 patients, the use of PIs may be accompanied by serious side effects, including AP. Two case reports[23, 24]have suggested a causal mechanism between PI-induced hypertriglyceridemia and AP, while a third case report of PI-associated acute pancreatitis was not associated with a rise in serum triglycerides[25]. It remains unclear whether PIs are associated with pancreatitis. Hence, it is important to recognize the associations between particular PI regimens and AP as well as the clinical features and develop an awareness of this adverse event among practitioners prescribing PI for the treatment of COVID-19 and other professionals, such as pharmacists and nurses. However, the assessment of PI-associated AP is quite challenging because of its low incidence and overlooked manifestations[21, 22]. Due to strict study entry criteria, relatively small sample sizes, and a finite scope and time frame, it is difficult to achieve this goal through experimental studies, including mandatory clinical trials, alone. Performing postmarketing surveillance is an efficient way to discover rare but potentially severe adverse reactions and help us acquire vital basis for prevention. Therefore, our study provides a profile of PI-associated AP through data mining of 33,832 adverse events related to PIs documented in the FAERS database.
Some prior studies that included patients receiving HAART found an association between female gender and AP and hypothesized that a smaller body weight might increase the toxicity of nucleotide reverse-transcriptase inhibitors (NRTIs) [35, 36]. However, Manfredi et al. found no association between gender and the risk of AP related to PI-based HAART exposure[21]. In our study, based on reports from the FAERS database, we found that PI-associated AP seemed to predominately affect men rather than women (64.56% vs. 28.42%). Most of these collected reports were from North America (40.35%) and Europe (30.88%), where women make up a smaller proportion of the HIV patient population[37]. Therefore, we could not conclude that men are more likely than women to suffer from AP following PI regimens. Further research is required to reevaluate the relationship between gender and PI-associated AP.
Guo et al. found that advanced age is a risk factor for acute pancreatitis after a retrospective cohort study of 4,972 patients with HIV infection, in which they found 159 cases of AP[38]. Conversely, we did not observe that PI-induced AP predominately affected elderly patients (11.93% of patients ≥65 years vs. 53.68% of patients < 65 years). On account of a lack of information in the FAERS database, it was difficult to control confounding factors such as age in this study. Further research is needed to explore the association between advanced age and the incidence of PI-related AP.
Previous studies have reported conflicting results regarding the impact of PIs on the development of pancreatitis[16]. Most evidence supporting the causal relationship of AP to PIs has come from case reports[23-25] and is insufficient to provide an overview of the risk of rare adverse events such as AP. Riedel et al. found that neither PI nor non-nucleoside reverse-transcriptase inhibitors (NNRTIs) are associated with an increased rate of AP through a ten-year cohort study[39]. Conversely, based on this pharmacovigilance analysis, 12 out of the 15 studied PIs were found to be associated with AP-related adverse events, which is similar to what was reported in some prior studies[21, 22]. Hypertriglyceridemia has been demonstrated to cause pancreatitis[40, 41]. According to previous studies, all available PIs are associated with significant increases in plasma triglyceride concentrations[42, 43], but hypertriglyceridemia is more frequently observed following the use of ritonavir or lopinavir/ritonavir combination therapy than following other PI-based combinations[44, 45]. Due to their potential clinicopathological consequences, ritonavir and lopinavir/ritonavir regimens may lead to an increased risk of hyperlipidemic pancreatitis[42, 46]. Surprisingly, we observed that indinavir, not ritonavir, seemed to have the strongest association with AP among all PI regimens, including ritonavir and lopinavir/ritonavir. This may be due to the relatively limited cases of AP-associated indinavir reported (8 reports). In our study, the 64.77% of reported cases are involving HIV-infected patients. As we know, antiretroviral treatment is very complex and dangerous due to concomitant medications and their toxic effects, including drug-induced AP. There are plenty of factors which can affect the pancreas, such as a previous history of AP, hepatobiliary diseases, alcohol abuse, low CD4 counts, and opportunistic infection prophylaxis, in addition to direct lesions caused by HIV[16]. All these factors make the evaluation of the association between PI and AP more difficult.
Another finding was that the median time to the onset of AP was 103 (IQR: 26-408) days after the initiation of PI treatment, which was similar to the onset time observed in some previous case reports[23-25]. Ritonavir/dasabuvir/ombitasvir/paritaprevir appeared to have the earliest onset of AP (31 [IQR: 17–68.25] days) among all studied PI regimens. For ritonavir and lopinavir/ritonavir, the median times to onset were 177 (IQR: 56-539) days and 91 (IQR: 22-352.5) days, respectively. It was suggested that ritonavir-based PI regimens may induce AP earlier than other PI regimens. Although the onset of AP after the use of PI seemed to be long according to some reports collected in this study, AP could occur as soon as after the first several doses of the ritonavir-based PI regimens mentioned above and atazanavir. Notably, triple combination therapy with ritonavir/lopinavir, ribavirin and interferon-alpha has been recommended as a drug treatment option by the guidelines, and it might be predominantly used to treat COVID-19 patients. However, both interferon monotherapy and interferon/ribavirin combination therapy have been reported in the literature to be causally associated with AP[47-48]. As a consequence of the multifactorial effects, triple combination therapy may lead to an increased risk of AP. Patients receiving PI regimens or the recommended triple combination therapy for the treatment of COVID-19 should be closely observed. Drug-induced AP should be considered, if patients present with clinical signs and symptoms of pancreatitis, including abdominal pain, nausea, vomiting, and conjunction with abnormal levels of serum lipase or/and amylase.
We also assessed and compared the fatality rates of AP associated with PIs to investigate differences in the severity of AP associated with various PIs. It was observed that AP was generally associated with poor outcomes, exhibiting a fatality rate of 14.02%, which was more than two times that found by Riedelet al. in a cohort study that followed 5,970 HIV-infected patients[39]. In that study, five patients died of pancreatitis during their hospitalization, yielding an in-hospital mortality rate of 5.9% for AP. As there is no consensus definition of acute pancreatitis, the different inclusion criteria used in the two studies may have resulted in different specificities and sensitivities of case inclusion. This may have caused the difference between the fatality rates in the two studies. Furthermore, we found that among all 271 reported PI-induced AP cases, compared with the other PIs, ritonavir (18.87%) and lopinavir/ritonavir (22.73%) appeared to be associated with a higher risk of death. However, based on the collected data, there was no significant difference in fatality rates across different PI regimens (Pearson's chi-square test for overall comparison, p=0.730). Fatal events occurred in 1 (25.00%) of 4 patients treated with saquinavir and 1 (20.00%) of 5 patients treated with nelfinavir; however, there were not enough cases reported to draw a conclusion, and continued surveillance is needed.
Based on spontaneous reporting systems (SRSs), disproportionality analysis and Bayesian analysis allow for signal detection rapidly and generate hypothesis about associations between AP and various PI regimens. However, it should be noted that in addition to many advantages, data mining techniques used in this study still have several limitations. First, affected by the inherent limitation of SRSs, sources of AP reports are non-homogeneous. Incomplete reporting, underreporting, false reporting, and inaccuracy might result in reporting bias and even misleading[49]. Second, owing to a lack of insufficient information in the FAERS database, the possibility of verification of the clinical findings justifying the reported AP is quite limited, and it is also scarcely possible to control such confounding factors as indications, pre-existing pancreatic diseases, comorbidities or other factors which might have an impact on AP occurrence[50]. Third, as reports extracted from the FAERS database do not reflect the total number of adverse reactions involving AP, the number of reports for a particular PI may be influenced by the extent of use of the product, which may be affected by some factors such as enterprise publicity and product price[49,50]. It cannot be used to quantify the incidence of PI-associated AP. Data mining techniques only provide a profile of PI-associated AP through signal detection. It is generally insufficient to prove the causal relationship, which needs to be replicated ideally by prospective studies[51].