Candida infection and Cryptococcus infection are prevalent fungal opportunistic infections in AIDS patients, and in southern China, Talaromyces marneffei(T. marneffei)-infection is also common [9]. For Candida infections, echinocandins and fluconazole are preferred over voriconazole [10]. For Cryptococcus neoformans infection, amphotericin B, flucytosine and fluconazole are often the preferred choice [11, 12]. For T. marneffei-infection, a fatal systemic mycosis, the recommended medication regimen is induction treatment with amphotericin B followed by a switch to maintenance oral itraconazole [13]. Therefore, voriconazole is not routinely recommended as the first choice for the common opportunistic fungal infections in AIDS patients. Previous studies have indicated that most isolates of T. marneffei are susceptible to voriconazole [14, 15]. Series studies evaluating the efficacy and the safety of voriconazole to treat patients with T. marneffei infection have demonstrated that voriconazole is an effective, well-tolerated therapeutic option for this kind of disease [15]. Voriconazole is also active against Candida and Cryptococcus. Therefore, voriconazole is a guideline-recommended alternative in Candida infection, Cryptococcus infection and T. marneffii infection [10–13]. In this study, we collected HIV cases for more than 3 years, voriconazole was frequently used as an alternative treatment for patients who were intolerant to other antifungal drugs. Thus, the number of HIV cases was relatively small in our study. Nevertheless, the rational use of voriconazole in AIDS patients is essential and of importance. 78.57% AIDS patients used voriconazole for targeted therapy and 21.43% for empirical treatment (Table 1). AIDS patients are a special population with special disease status and polypharmacy, so the individualized medicine of voriconazole in a clinical setting become more challenging. Series studies have investigated the application of voriconazole TDM in special populations, including children [16], the elderly [17], patients with cirrhosis [11], patients with tuberculosis [18]. However, no literature has reported the application of voriconazole TDM in AIDS patients, which is the outstanding highlight of this present study. Moreover, the clinical pharmacist was involved in the whole treatment, for example, took part in selecting appropriate drugs and formulating treatment regimens for AIDS patients, conduct voriconazole TDM, guide the dose adjustment of voriconazole based on TDM and monitoring of ADRs. Therefore, clinical pharmacist can play an important role in the treatment of AIDS. Besides, clinical pharmacist has emerged as an indispensable member of the multidisciplinary diagnosis and treatment team.
The therapeutic range of trough concentration and the applicable population for voriconazole TDM are still controversial [19]. The voriconazole treatment regimens for 26 cases are all given a loading dose and a maintenance dose based on body weight. The maintenance dose was not halved in 2 patients with hepatic function Child-Pugh class B. Blood samples from the 28 cases were collected 0.5 h before the 5th dose at the earliest, and the average sampling time was 4.25 d after initiation of voriconazole therapy, the timing of blood sampling in the 28 cases all met the guideline requirements [4–8], which ruled out the influence of improper sampling on the TDM results. However, the first results of voriconazole TDM showed that the concentration attainment rate is only 57.14%(Table 2). Recently, there have been plenty of researches about the application of voriconazole TDM on patients with invasive fungal infections, but the patients in our study have a lower attainment rate of concentration compared with other research [20]. Dose adjustment based on TDM is an important element of individualized drug monitoring, and domestic and foreign clinical guidelines have different recommendations. Chinese guideline recommend that 20% maintenance dose can be reduced when the concentration reach above the upper limit and below 10.0 µg/mL and no grade 2 or higher adverse events occurred [8]. Moreover, 50% maintenance dose can be increased when the concentration are below the lower limit or when voriconazole treatment shows suboptimal efficacy [8]. In this study, AIDS patients who did not achieve target concentration range were adjusted to individualized regimens based on TDM results, including avoidance of drugs carrying a high risk of drug-drug interactions, appropriate dose increment or reduction, or switching to alternative regimens. There are three patients in this study reduced the dose by 20%(Table 3). Also, the dose was increased by 20% in another patient since a trough concentration of 0.9µg/mL was measured from the first TDM(Table 3). After individualized intervention, the trough concentration of voriconazole in aboved four patients all reached the standard range as second TDM indicated(Table 3), demonstrating that the Chinese dose adjustment guideline is applicable to the population of AIDS patients. Furthermore, more attention should be paid to the patient’s compliance and prompt withdrawal of the interacting drugs other than dose adjustment, according to British guideline [5]. After discontinuation of rifampin, the voriconazole concentration of one patient in our study also rise to the lower limit without dose adjustment (Table 3). Consequently, the attainment rate of trough concentration increased significantly after intervention based on first TDM results, from 57.14–87.50%(Table 2). Thus, there is significant need to perform TDM for AIDS patients using voriconazole.
A meta-analysis showed that the risk of developing drug toxicity could be significantly increased when trough concentration of voriconazole exceed 6.0 µg/mL.2 During hospitalization, the incidence of voriconazole associated ADRs is 21.43% in our study(Table 4). 83.33% of the patients suffering from ADRs had trough concentrations above 5.0 µg/mL, manifesting as hallucinations, visual disturbances and drug-related hepatitis(Table 4). The mean trough concentration of voriconazole in the ADR group was (7.12±2.27) µg/mL. It is worth mentioning that the incidence of ADR exhibits positive correlation with the trough concentration level of voriconazole (P=0. 017).
There are many multifactorial and complex affecting factors that can influence the individual differences in clinical application of voriconazole, and the factors that have been confirmed include genotype, age, gastrointestinal absorptions, pathophysiological status and drug interaction, of which Cytochrome P450 2C19(CYP2C19) genetic polymorphisms and drug interaction are the two most important affecting factors [17, 21]. The Cmax and AUC values of voriconazole in poor CYP2C19 metabolizers are 2-5 times higher than normal CYP2C19 metabolizers [22]. The CYP2C19 genetic polymorphism influences the steady-state level of voriconazole and is a significant affecting factor contributing to the highly variable pharmacokinetics of voriconazole [23]. The detection of CYP2C19 genetic polymorphism is recommended for patients using voriconazole by Clinical Pharmacogenetics Implementation Consortium (CPIC) [24]. It is worth mentioning that the distribution characteristics of CYP2C19 genetic polymorphisms can differ by race and ethnicity. About 20-30% Asian populations are slow metabolizers, while only about 2-3% Caucasians are slow metabolizers [25]. For 32.14% of the AIDS patients in this study, the mean trough concentration of voriconazole skewed toward higher values(Table 2), and the observed phenomenon may be blamed for genotype. Nevertheless, the present study suffered from a drawback that the patients were not subjected to detection of CYP2C19 genetic polymorphisms.
Drug interaction is another important affecting factor on steady-state level of voriconazole. AIDS patients are immune-suppressed and susceptible to opportunistic infections, so polypharmacy is often required. Thus, there is clearly a need to be more alert to the potential drug interactions. Voriconazole is metabolized mainly in liver, both an inhibitor of CYP2C19, CYP2C9, CYP3A and an enzyme substrate. So voriconazole can easily interacts with other CYP enzyme substrates, inhibitors or inducers. The common drugs observed drug-drug interactions with voriconazole include antiretroviral drugs, antiepileptic drugs, PPIs, rifamycin, antibacterial drugs, glucocorticoids, calcium channel antagonists, sedative hypnotics, antiarrhythmic drugs and so on. CYP inducers can reduce systemic exposure to voriconazole and lead to treatment failure when trough concentration of voriconazole are below the therapeutic range [26]. Rifampicin, a CYP3A4 inducer, can dramatically decrease the Cmax and AUC of voriconazole in vivo [27]. In our study, a patient diagnosed co-infection with mycobacterium tuberculosis and T. marneffei was co-administrated with voriconazole during quadruple antituberculosis therapy for pulmonary tuberculosis (isoniazid, rifampin, ethambutol and pyrazinamide). The dosage of voriconazole and the timing of sampling were in accordance with guideline recommendations. Unexpectedly, the voriconazole trough concentration was measured to be 0.2µg/mL, which was far below the lower limit of the therapeutic range. After discontinuation of rifampicin for 7 days, the voriconazole trough concentration rised to 1.0µg/mL without dose adjustment, which was within therapeutic range. Our results further confirmed the potent enzyme-inducing effect of rifampicin on the trough concentration of voriconazole. In contrast, co-administration with CYP inhibitors may increase systemic exposure to voriconazole and alter its safety profile [2]. When trough concentration of voriconazole is above the therapeutic range, an increased incidence of ADR may occur during voriconazole therapy [2]. The most common drugs in combination with voriconazole in this study are PPIs. Surprisedly, there were no effects of esomeprazole or omeprazole on voriconazole trough concentration could be significantly observed between the no-combination group and the co-administered with PPIs group(P=0.76). Since this study is a retrospective study in a single center, and the number of cases is relatively small, there is an inherent problem in studying drug interactions, especially co-administration of CYP inhibitors including PPIs.
The specific pathophysiological status of AIDS patients is considered another important factor influencing the steady-state level of voriconazol in blood. AIDS patients are prone to develop hypoproteinemia during treatment, which may also bring about alterations in pharmacokinetic and pharmacodynamic properties of voriconazole. It is well known that the bound drug-albumin complex is the storage form of a drug, and the complex can gradually release free drug when the blood concentration decreases. On one hand, only the unbound or free fraction of a drug can cross the biological membrane and exert pharmacological effects within the body. On the other hand, only the unbound or free fraction of a drug can be cleared from the body. Therefore, serum ALB level will have a significant effect on the apparent volume of distribution (Vd) and clearance (CL) of highly albumin-bound drugs. Some studies have demonstrated that hypoproteinemia is an influential factor affecting trough concentration of voriconazole [28]. On the one hand, hypoproteinemia can result in increased Vd and CL of a drug, potentially resulting in under-dosing and consequent treatment failure. On the other hand, hypoproteinemia can alter the plasma protein-binding rate of voriconazole, potentially resulting in increased concentration of unbound voriconazole and consequent ADRs, even when the trough concentration of voriconazole is within normal range [28]. One patient with a trough concentration within the therapeutic range, mainly manifested as anxiety and insomnia(Table 4), requiring consideration of hypoproteinemia(ALB=28.4g/L). The mean ALB of AIDS patients in this study was (28.58±5.03) g·L−1, and the ALB level appeared to be a important factor affecting steady-state level of voriconazole in blood (Table 5, P=0.006). Furthermore, multiple linear regression analysis also indicate that 40.6% variations of voriconazole trough concentration can be attributed to differentiation of gender, age, ALB, drug interactions and AST(Table 5, R2=0.406).