As far as we know, this is the first comparative safety study on FAERS that aimed to assess the reported AEs of darunavir and its boosted agents. Overall, four main findings emerged: (1) AEs related to darunavir exposure involve various organs or tissues, although some AEs occur more commonly than others. We found statistically significant signals in the liver, kidney, metabolic and nutritional system, endocrine system, eye, cardiac system, musculoskeletal system, nervous system, skin, and gastrointestinal tract. (2) Strongly positive signals related to mitochondrial toxicity and eye disorders (included diplopia, eyelid ptosis, and progressive external ophthalmoplegia) were revealed for the very first time. (3) The use of darunavir-containing agents may be related to some rare but severe AEs such as acute pancreatitis, serious dermatologic reactions (Stevens-Johnson Syndrome and exfoliative dermatitis) and angioedema.(4)Although darunavir is widely used in pregnant women, signals for adverse pregnancy outcomes (preterm birth, miscarriage, fetal growth restriction, low birth weight, stillbirth, premature rupture of fetal membranes, and abnormal umbilical cord) were detected in our study, which highlights its safety concern during pregnancy.
Hepatotoxicity is one of the commonly monitored safety profiles for darunavir during clinical practice4,8. According to the previous studies, some degree of serum aminotransferase elevations occurred in a high proportion of patients taking darunavir containing antiretroviral regimens. Moderate-to-severe elevations in serum aminotransferase levels are found in 3–10% of patients overall. Acute liver injury due to darunavir has been reported and the pattern of serum enzyme elevations is usually hepatocellular8. Our study uncovered positive signals for hepatocellular injury and elevation in serum hepatic enzymes which were consistent with the previous findings. Apart from hepatocellular injury, we also found darunavir can induce increased bilirubin, cholestasis, and jaundice which were not observed in clinical studies. In 2019, Yancheva N.9 reported a case of darunavir-related cholestatic hepatitis in an HIV patient in the third year of his combined antiretroviral therapy, and discontinuation of darunavir resulted in a progressive decrease in liver enzyme and bilirubin level. The cause of the hepatobiliary disorders from darunavir is not clearly known. The toxic intermediates may be the cause of some liver injury. It is worth noting that, except for hepatocellular injury, cholestasis should also be monitored when darunavir is prescribed. In co-infected individuals with hepatitis B or C, initiation of darunavir-based therapy lead to exacerbation of hepatitis B or C and serum aminotransferase elevations which need to be monitored prospectively10.
HIV infection has been associated with both acute kidney injury (AKI)11 and chronic kidney disease (CKD)12. It is hypothesized that HIV-associated nephropathy (HIVAN) involved direct infection of kidney epithelial cells by HIV with subsequent expression of HIV genes in a genetically susceptible host. The introduction of ART has reduced the incidence of end-stage renal disease (ESRD) attributed to HIVAN. A recent study suggested that darunavir can directly prevent kidney injury by suppressing HIV-induced up-regulation of immune response genes in human kidney cells which were independent of inhibition of HIV protease. Nevertheless, in our study, 6 positive signals of the renal and urinary system were detected, which presented as AKI, renal impairment, blood creatinine increased, glomerular filtration rate decreased, proteinuria, and renal tubular necrosis. It was showed that cobicistat inhibits tubular secretion of creatinine without affecting actual renal glomerular function13. This should be considered when interpreting changes in blood creatinine in patients initiating darunavir/cobicistat. Besides, our study uncovered an association of darunavir with rhabdomyolysis, which might be one of the causes of kidney injury. On the other hand, we should take caution explaining the significant signal of darunavir in renal injury. Since HIVAN is one of the complications in advanced HIV disease, the main manifestations of which were heavy proteinuria and a decline in kidney function14. In accord with this assumption, drug resistance and treatment failure are significantly noted in the analysis, which implicated the occurrence of advanced HIV disease.
Our findings showed a disproportionate association with hypertriglyceridemia, hypercholesteremia, and hypokalemia. It was consistent with the previous findings that exposure to certain PIs can cause an adverse change in the lipid profile15. One study suggested that ritonavir-boosted darunavir and atazanavir rather than raltegravir lead to increases in total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C)16. In a pooled subgroup analysis of the clinical trials of boosted darunavir, 15% of patients developed elevated triglyceride levels compared with 7% percent in the comparator PI arms17. Baker also suggested that initiation of ARTs (including darunavir) increased the levels of total cholesterol and LDL-C18.
The signal of lipodystrophy, which has been associated with abnormalities in glucose and lipid metabolism, was extremely strong in our study. Lipodystrophy can be manifested as lipoatrophy or fat accumulation, and it was estimated that 10–80% of HIV patients developed these changes19,20. Data suggested that exposure to certain nucleoside reverse transcriptase inhibitors (NRTIs) is the major factor associated with lipoatrophy20. Some studies showed that PIs may act synergistically with NRTIs21, and therapy with PIs alone does not appear to lead to lipoatrophy22. Fat accumulation has been described since the introduction of combination ART, which was initially thought to be lead by the use of protease inhibitor therapy23. However, in studies that have replaced PIs with alternative ART, there has been no observed decrease in visceral fat24. A study showed that body fat tissue increased in patients on darunavir/ritonavir monotherapy and darunavir/ritonavir plus NRTIs, with no difference between the arms25.
Hyperglycemia is another positive signal identified in our study. In animal models, studies of HIV-negative volunteers given PIs, and clinical trials of PIs have all demonstrated insulin resistance with these agents26. One possible explanation for the association is that PIs can direct down-regulation of the glucose transporter-4, the major transporter of glucose into fat cells, and cardiac and skeletal muscle27. It was suggested that darunavir-based ART in those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases28. Since HIV-positive persons are at increased risk for premature cardiovascular disease (CVD)29, and atherosclerotic disease accounts for a substantial proportion of HIV-related CVD, dyslipidemia and hyperglycemia caused by darunavir can adversely affect the risk factors for CVD. However, the association between darunavir or atazanavir administration and increased risk of myocardial infarction or stroke has not been established which was seen with other agents from this class30.
Hypokalemia (serum potassium ༜ 3.5mEq/L) is common in AIDS inpatients, usually due to infectious diarrhea, vomiting, or AIDS-related intestinal disease31. Hypokalemia directly caused by darunavir has not been reported, but it was suggested that diarrhea and vomiting were the most common adverse reactions of darunavir28, which we presumed might to be the cause of hypokalemia.
Adrenal suppression and adrenal dysfunction were found related to the use of darunavir-containing agents. In the early AIDS epidemic, adrenal disorders in HIV-infected individuals were often a consequence of opportunistic infections, neoplasms, or concomitant systemic illness, the morbidity of which declined rapidly due to potent antiretroviral therapy. The possible explanation of darunavir-containing agents induced adrenal disorder identified in our study may be due to drug-drug interaction of pharmacokinetic boosters with exogenous glucocorticoids32. Glucocorticoids, including nasal, inhaled, intra-articular, or topical ocular preparations, were widely used in HIV patients for non-AIDS-related conditions that occur more frequently and at a younger age than in uninfected persons33. Iatrogenic Cushing's syndrome can result from the co-administration of ritonavir or cobicistat and synthetic glucocorticoids given by any route34,35. The effects of these boosters on cytochrome P450 lead to prolongation of the half-life of the latter. The resultant high plasma levels of glucocorticoid cause Cushing's syndrome and suppression of endogenous adrenocorticotrophic hormone and secondary adrenal insufficiency. In a retrospective study of 171 patients, 9 cases developed secondary adrenal insufficiency after receiving ≥ 1 local steroid injection, all of which occurred among the 81 patients on PIs36. Corticosteroid regardless of the route should be used with great caution and close monitoring in HIV-infected patients on PIs.
Our study revealed a strong association of mitochondrial toxicity and darunavir (ROR = 171.92, PRR = 136.03, IC = 6.08) that has not been reported previously. Mitochondrial toxicity has been recognized as a major adverse effect of the treatment of HIV infection with NRTIs37, but not darunavir or other PIs. The clinical expression of mitochondrial disorders is extremely variable, and organs and tissues highly related to oxidative phosphorylate (muscles and neuro for instance) are mostly easily involved. Muscle symptoms included exercise intolerance, fatigue, muscle weakness, elevated serum creatine kinase, myalgia, or, less often, rhabdomyolysis38. It is not surprising to find that, increased creatine phosphokinase and rhabdomyolysis are both positive signals in our study, which were presumed to be the clinical expression of mitochondrial toxicity of darunavir. Increased creatine phosphokinase and rhabdomyolysis were recorded adverse events in the label, and our study provided a possible explanation for the cause of these AEs.
Another novel AEs inferred to be associated with mitochondrial toxicity of darunavir were eye disorders39, and they included diplopia, eyelid ptosis, and progressive external ophthalmoplegia (PEO). Among them, the signal of PEO showed a significantly high strength (ROR = 1761.17,PRR = 1753.15༌IC = 3.54). PEO is a myopathic alteration of slow progression which affects extrinsic ocular muscles; ptosis of the eyelid being the most characteristic sign. Some cases present as eyeball movement disorder, and progress to immobilization of the eye. PEO can be induced by trauma, toxin, heritable disorder, degeneration, and masses, and is one of the clinical phenotypes of mitochondrial myopathies40. We speculated that darunavir induced eye disorders through mitochondrial toxicity, although the relationship had to be confirmed with rigorous studies.
There is little doubt that mitochondrial toxicity is the major cause of NRTIs-induced myopathy, and neuropathy41, and we can't help but speculate the newly found AEs with nervous system disorders (neuropathy and peripheral neuropathy) of darunavir in our study might also be related to mitochondrial toxicity. However, this speculation needs to be further investigated. While the pathogenesis of NRTIs induced mitochondrial toxicity has been well known, which is by inhibiting mtDNA enzyme polymerase-gamma, thus resulting in organelle dysfunction and impairment of oxidative phosphorylation42, the mechanism of PIs induced mitochondrial toxicity has not been revealed.
In our study, we found generalized rash, pruritus, exfoliative dermatitis and Stevens-Johnson Syndrome (SJS) were positive signals in the skin and subcutaneous tissue. In clinical trials, rash (all grades) occurred in 16% of subjects treated with darunavir. Rashes were generally mild-to-moderate, self-limited maculopapular skin eruptions43. Severe skin rash, including erythema multiforme and SJS has also been reported, with some accompanied by fever and elevations ofaminotransferase44. The discontinuation rate due to rash was 0.3%28. SJS are severe mucocutaneous reactions, most commonly triggered by medications. The incidence of SJS is 100-fold higher among HIV individuals than in the general population45. The reasons for the susceptibility are not fully understood, although exposure to multiple medications, immune dysregulation, and the presence of concomitant infections may contribute46. Our study brought to the forefront again the risk of severe adverse skin reactions caused by darunavir, which should be closely monitored.
Our study identified diarrhea, gastrointestinal disorder, esophageal candidiasis, and acute pancreatitis as positive signals in the gastrointestinal system. Diarrhea is one of the most commonly reported adverse reactions for darunavir, involving more than 10% of individuals47. Esophageal candidiasis, which is typically seen in patients with HIV who have advanced immunosuppression, may not be directly related to the administration of darunavir, but rather to the failure of antiviral therapy48. This inference is supported by the finding of the two strongly positive signals of drug resistance and therapy failure in our study. Acute pancreatitis induced by darunavir-based ARTs has been reported previously49. Hypertriglyceridemia and hypercholesteremia related to darunavir may play a role in the occurrence of acute pancreatitis. Besides, it was suggested that mitochondrial toxicity may be the cause of NRTI-induced pancreatitis50, the possibility cannot be ruled out that acute pancreatitis is one of the manifestations of darunavir-induced mitochondrial toxicity.
Protease inhibitors have been a key component of HIV therapy in pregnant women for about 25 years. In 2016 DHHS guidelines, darunavir/ritonavir replaced lopinavir/ritonavir as a recommended agent due to its potent antiretroviral activity, low propensity for resistance development, and a lower rate of causing lipid abnormality during pregnancy51. It was found that the fetal transfer rate of darunavir was 12–16%, and a mean concentration of 132 ± 32ng/mL was identified in the fetal compartment52. Although fetal concentrations are much lower than those in maternal plasma, this can still expose the fetus to a significant concentration of the drug. Such exposure may provide the benefit of pre-exposure prophylaxis, but it could also lead to toxicity. Although teratogenicity has not been identified in animal studies28, no well-designed controlled trials have been performed in humans. The antiviral pregnancy registry reported that the risk of birth defects did not increase following darunavir exposure53, and darunavir could even play a protective role in the development of microcephaly in children who were HIV-exposed but uninfected54. Our study showed strongly positive signals for darunavir in terms of premature baby, spontaneous abortion, foetal growth restriction, low birth weight baby, stillbirth, premature rupture of membranes, and umbilical cord abnormality. In the previous studies, preterm birth and low birth weight were the most commonly reported adverse events after pregnancy exposure to PIs55,56. One study suggested that prematurity was independently associated with ritonavir-boosted PI therapy during pregnancy57. We further detected signals for darunavir/ritonavir and darunavir/cobicistat respectively, identifying positive signal for darunavir/ritonavir only in prematurity, and darunavir/cobicistat in abortion spontaneous and feotal growth restriction. The result further verified that preterm birth may be more associated with ritonavir. Since the combination of darunavir/cobicistat is not currently recommended during pregnancy due to a lack of pharmacokinetic and safety data for cobicistat in pregnant women51, the difference of these two combinations for the offspring need to be further studied.
The data mining of FAERS database is considered to be a valuable tool to evaluate the medication safety profile. Despite some steps were taken to make the results more reliable, such as report cleaning and utilizing three methodologies to reduce the incidence of false-positive signals, the following limitations of our study need to be noticed: (1) we derived ROR, PRR, and IC values based on the reported frequency of drug-event combinations for the studies drug, and were adjusted based on the rates reported by other drugs and the rates of all other AEs reported for the studied drug. The value indicated an increased risk of AE reporting and not a risk of AE occurrence. (2) The FAERS database is subject to various biases such as under-reporting, over-reporting, duplicates, unverified source of submitted data, missing information. (3) The certainty that the drug is in fact responsible for the reported event is absent. This is particularly true for antiretroviral agents in HIV patients since HIV infection per se can induce a higher risk of multi-system complications and are generally treated with a combination of antiviral drugs. (4) Except for pregnancy and perinatal conditions, the signal mining was not carried out separately for darunavir, darunavir/ritonavir, and darunavir/cobicistat, making it impossible to distinguish AEs resulted from darunavir and boosters.