Efficacy and toxicity analysis of ganciclovir in patients with cytomegalovirus lung infection: what is new for target range of therapeutic drug monitoring

doi:10.21203/rs.3.rs-5287410/v1

Objectives

To investigate the relationship between ganciclovir trough concentration and its clinical efficacy and safety in patients with pulmonary cytomegalovirus (CMV) infection. To evaluate the target value of therapeutic drug monitoring (TDM) for predicting clinical efficacy or toxicity.

Methods

An observational study was conducted on patients with CMV lung infection between Jan 2021 and Dec 2023. Target trough ganciclovir concentrations were collected during TDM and clinical outcomes and adverse events (AEs) were assessed. Multiple regression analyses or binary logistic regression were used to analyze the factors affecting ganciclovir trough concentrations and clinical efficacy. Receiver operating characteristic (ROC) curve analysis identified ganciclovir trough concentration cutoffs as predictors of toxicity.

Results

Of 149 included patients, only 19.22% of trough concentrations reached the target range of 2–4µg/ml. Diabetes, organ transplantation, and elevated hemoglobin levels decrease trough concentrations, whereas elevated blood creatinine and continuous renal replacement therapy (CRRT) increase trough concentrations. No relationship was found between the trough concentrations and clinical outcomes. Organ transplantation, duration of ganciclovir administration, and albumin levels affect the clinical efficacy. ROC analysis identified ganciclovir trough concentrations of 0.985 µg/ml (AUC = 0.600) and 0.995 µg/ml (AUC = 0.701), associated with decreased hemoglobin and elevated blood creatinine levels, respectively.

Conclusions

No association was observed between ganciclovir trough concentration and clinical efficacy. However, thresholds for ganciclovir trough concentrations causing decreased hemoglobin and increased blood creatinine levels were identified. Renal replacement therapy is more likely to lead to elevated trough concentrations of ganciclovir. These findings suggest the importance of TDM for ganciclovir, and new target range should be considered.

Ganciclovir

Cytomegalovirus

Lung infection

therapeutic drug monitoring

trough concentration. Clinical efficacy

Toxicity

Human cytomegalovirus (HCMV) primarily affects immunocompromised individuals or causes congenital infections, leading to pneumonia [1]. Hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients, along with HIV patients, are particularly vulnerable to HCMV pneumonia [2]. Though rare, it can also occur in immunocompetent individuals [3, 4]. A Korean cohort study [3] reported higher all-cause mortality in non-transplant CMV patients compared to SOT recipients, indicating severe outcomes beyond severely immunocompromised transplant recipients. Intravenous ganciclovir and oral valganciclovir are the main antiviral treatments for CMV [5]. In healthy individuals with normal renal function, ganciclovir trough plasma concentrations(Cmin) were 1 µg/ml at 11 hours for a 5 mg/kg dose and 0.6 µg/ml at 7 hours for a 2.5 mg/kg dose [6]. Ganciclovir clearance, 91% renal, is highly dependent on renal function [7]. In SOT recipients, ganciclovir clearance correlates with renal function, requiring dosage adjustments based on glomerular filtration rate [8]. The most significant adverse effect is myelosuppression. In marrow transplant recipients, neutropenia (ANC < 1,000/µL) occurs in 41–58% of patients treated with ganciclovir [9], while in SOT patients, it is about 10%. In advanced HIV patients, severe neutropenia (ANC < 500/µL) occurs in 34% treated with ganciclovir.

Therapeutic drug monitoring (TDM) can improve drug efficacy and reduce adverse effects. The role of TDM in optimizing ganciclovir remains debated [8], yet several centers have adopted TDM programs [10–12]. Ganciclovir's narrow therapeutic window associates higher concentrations with toxicity [13–16]. Adequate treatment is crucial, especially for patients with high viral loads to prevent resistance [17]. TDM assists in assessing serum concentrations and guiding dosage adjustments [11]. In vitro data suggest serum concentrations of 0.26 to 1.28 µg/ml inhibit CMV replication by 50% [18]. The University Medical Center Groningen targets plasma trough concentrations (Cmin) of 2–4 mg/L for therapeutic ganciclovir [11]. Most studies on ganciclovir TDM focus on transplant recipients, with limited research on the broader adult population. A recent study [10] on TDM in adult CMV infection found no clear link between drug exposure and clinical efficacy or safety, similar to findings in transplant recipients [19]. Another study [20] reported a significant correlation between ganciclovir AUC or Cmin and decreased leukocytes and increased blood creatinine, without quantitative analysis. An in vitro study [21] showed increased toxicity in lymphoblastoid cells after 14 days of ganciclovir exposure. No studies have proposed pharmacokinetic/pharmacodynamic(PK/PD) targets or identified TDM cut-off values predicting clinical efficacy or toxicity [22].

This study focused on adult patients with pulmonary cytomegalovirus infections. The objectives were to evaluate factors affecting ganciclovir Cmin, examine its association with clinical efficacy and toxicity, and perform exposure-efficacy analyses to establish a TDM target value for predicting clinical outcomes.

1.Study design and ethics

Patients with CMV pneumonia who underwent ganciclovir TDM from Jan 2021 to Dec 2023 at China-Japan Friendship Hospital were retrospectively analyzed. Inclusion criteria were: (1) age ≥ 16 years, (2) CMV circulating threshold (CT) is positive in broncho alveolar lavage(BAL) test, and (3) ganciclovir IV therapy with routine TDM. Exclusion criteria included: (1) ganciclovir Cmin not at steady state and (2) incomplete laboratory or efficacy data.

This study was approved by the Ethics Committee of China-Japan Friendship Hospital (No.2023-KY-270). Informed consent was obtained from all patients.

2. TDM strategy

Routine TDM testing was performed after at least three regular doses, ganciclovir Cmin were collected 30 minutes before the next dose. Plasma ganciclovir concentration was determined using a validated LC-MS/MS method. Ganciclovir-d5 internal standard solution (20µL) was added to 400µL of plasma, followed by 600µL of acetonitrile. After shaking and centrifugation, 900µL of the supernatant was transferred to a new tube, mixed with 400µL of dichloromethane, and centrifuged again. The supernatant (0.2µL) was injected into the LC-MS/MS system equipped with a BEH C18 column (50 × 2.1 mm, 1.7 µm, Waters, USA). The mobile phase consisted of 2 mM ammonium acetate and 0.1% formic acid in water, and acetonitrile with 0.1% formic acid. In MRM mode, ions monitored were m/z 256.0→135.0 for ganciclovir and 261.0→135.0 for ganciclovir-d5. The concentration range was 0.3125-20µg·mL^-1, excluding concentrations below 0.3125µg·mL^⁻¹.

3.Clinical data collection

For all patients, the following data were collected: gender, age, weight, disease, type of transplant, presence of renal replacement therapy [continuous renal replacement therapy (CRRT) or intermittent renal replacement therapy (IRRT)], administration route, dose, duration, and the start and stop dates of ganciclovir medication. Laboratory values, including CMV CT, ganciclovir Cmin, white blood cell count (WBC), neutrophil count (NEUT), platelet count (PLT), hemoglobin (HGB), total bilirubin (TBIL), alanine aminotransferase (AST), aspartate aminotransferase (ALT), serum creatinine (SCr), and creatinine clearance (CRCL) (calculated using Cockcroft-Gault).

4.Target range of Cmin, clinical efficacy, adverse effects

Target range of Cmin: Our institution recommends a Cmin range of 2.0 to 4.0 µg/ml for therapeutic ganciclovir use.[11]

Clinical efficacy: Treatment efficacy was defined by an increase or negative in CMV CT, whereas a decrease indicated treatment failure.

Adverse reactions: Hepatic and renal functions were evaluated using ALT, AST, TBIL, and SCr levels. Increases were calculated by subtracting baseline levels from end-of-dose levels. An increase to twice the upper limit of normal at the end of dosing was deemed an adverse drug reaction. Myelosuppression was assessed through decreases in WBC, NEUT, PLT, and HGB, calculated as the difference between end-of-dose and baseline measurements. Adverse drug reactions were defined as a 20% decrease in WBC, 20% decrease in NEUT, 50% decrease in PLT, and 20% decrease in HGB levels.

5.Statistical analysis

Numerical variables are summarized with medians and IQRs, while categorical variables use frequencies and percentages. Data normality was assessed before the correlation test to choose between parametric (Pearson’s test) or non-parametric (Spearman’s test) analyses. One-way ANOVA analyzed group differences. Multiple linear regression or binary logistic regression identified influencing factors. Receiver operating characteristic(ROC) curve analysis was performed by selecting the average Cmin of ganciclovir, calculating AUC, and the 95% CI. Data analysis was conducted using IBM SPSS Statistics 25 (IBM SPSS, Chicago, IL, USA) and GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA). In multivariate analyses, P values < 0.05 were deemed statistically significant.

1. Demographic information

Between Jan 2021 and Dec 2023, 149 patients (281 concentrations) were enrolled in the study. The median age was 65, with 103 males (69.13%). Among them, 29 were solid organ transplant recipients (19.46%): 21 lung, 7 renal, and 1 liver transplant. Only 1 patient had an allogeneic hematopoietic stem cell transplant (0.67%). The median initial CMV CT was 24.23. All patients were treated with intravenous ganciclovir for cytomegalovirus infection, with a median daily dose of 300 mg and 5.17 mg/kg. Patient details are provided in Table 1.

Table 1.Patient characteristics(n=149)

Characteristics	Value^a
Age,years)	65（16-89）
Sex(male,%）	103（69.13）
Weight,kg	60（35-100）
Immunodeficiency background
Malignant tumor	14（9.40）
Allogeneic stem cell transplantation	1（0.67）
Solid organ transplant	29（19.46）
Lung	21（14.09）
Kidney	7（4.70）
Liver	1（0.67）
Cytomegalovirus (CMV)
Initial BAL CMV replication	149(100%)
Baseline CMV CT	24.23（12.78-28.23）
Baseline biochemical data
White blood cell count，10⁹/L	9.26（0.43-37.95）
Neutrophil count，10⁹/L	7.49（0.34-32.22）
Platelet count，10⁹/L	163（6-599）
Hemoglobin，g/L	85（40-171）
SCr，μmol/L	70.40（6.80-426.00）
Creatinine clearance，ml/min^b	76.27（11.14-651.59）
Days of hospitalization, days	26（7-369）
Daily dose，mg	300（50-1000）
Daily dose corrected by weight，mg/kg	5.17（0.91-15.38）

^aData are presented as frequency (%) unless denoted as mean ± standard deviation or median (IQR).

^bCalculated using the Cockcroft-Gault equation.

2. Overview of therapeutic drug monitoring

Among the 281 ganciclovir concentrations, the maximum was 11.94 μg/ml, the minimum was 0.07 μg/ml, and the mean±SD was 1.78±1.93 μg/ml. The concentrations were categorized into three groups: <2 μg/ml, 2–4 μg/ml, and >4 μg/ml. A total of 54 cases (19.22%) were within the target range, with <2 μg/ml comprising the highest percentage (70.82%) (Table 2).

Table 2. Distribution of cases of Cmin by level

Concentration range（μg/ml）	Cases	Proportion（%）	Concentrations （mean±SD,μg/ml）
＜2	199	70.82	0.87±0.53
2~4	54	19.22	2.68±0.52
＞4	28	9.96	6.54±2.12

3. Relationship between ganciclovir Cmin and patient prognosis

After ganciclovir treatment, 102 patients (68.46%) had negative CMV results, and seven (4.70%) had elevated CMV CT, resulting in a 73.15% overall treatment efficiency. No significant association was found between ganciclovir Cmin and CMV prognosis (P=0.311). When categorizing CMV prognosis into CT lowering, increase, and negativization, the drug Cmin and C/D in the CT lowering group were lower than those in the negativization and CT elevated groups, but without significant difference (P=0.347, P=0.623) (Table 3).

Table 3.Relationship between ganciclovir concentrations and patient outcomes

Outcome	Trough concentrations（μg/ml）	Standardized drug trough concentration（μg/ml/g）
CMV negativization	1.76±1.88	8.41±13.96
CMV circulating threshold increase	1.93±2.16	9.89±17.93
CMV circulating threshold lowering	1.04±0.81	5.79±7.56
F	1.064	0.474
P	0.347	0.623

Binary logistic regression analysis (Table 4) revealed that organ transplantation (OR 0.247, 95% CI: 0.093-0.654) negatively impacted CMV prognosis, while extended ganciclovir administration (OR 1.095, 95% CI: 1.019-1.176) and higher patient albumin levels (OR 1.101, 95% CI: 1.043-1.161) were associated with better clinical outcomes in CMV.

Table 4 Binary logistic regression of factors influencing the clinical efficacy of CMV

Variable	Regression Coefficient	Standard Error	Wald χ2	Odds Ratio (OR)	95% Confidence Interval (CI) for OR	p Value
Sex	0.320	0.444	0.521	1.377	0.577~3.285	0.471
Age, yr	0.006	0.014	0.183	1.006	0.979~1.034	0.669
Weight, kg	-0.012	0.016	0.521	0.988	0.957~1.021	0.470
Hospital stay, d	-0.008	0.008	0.978	0.992	0.977~1.008	0.323
Diabetes	-0.641	0.395	2.626	0.527	0.243~1.144	0.105
Transplantation	-1.400	0.498	7.906	0.247	0.093~0.654	0.005^*
Daily dose, mg	-0.001	0.001	1.900	0.999	0.997~1.000	0.168
Duration of therapy, d	0.090	0.037	6.053	1.095	1.019~1.176	0.014^*
Albumin, g/L	0.096	0.027	12.280	1.101	1.043~1.161	0.000^*

Dependent Variable: The effectiveness of ganciclovir treatment was determined by CMV negativization or increased circulating threshold (CT) (value = 1), while decreased CMV circulating threshold post-treatment indicated ineffectiveness (value = 0).

Note:*P < 0.05

4.Effect of renal function, RRT on plasma drug concentration

In this study, 281 plasma concentrations were recorded including 62 cases (22.06%) with CRRT and 7 cases (2.49%) with IRRT. Data were divided into CRRT, IRRT, and no renal replacement therapy (no-RRT) groups. The Cmin was significantly higher in the CRRT group (2.72±2.71μg/ml), compared to the no-RRT group (1.47±1.51 μg/ml, P < 0.0001) and slightly higher than the IRRT group (2.65±2.27μg/ml), though not statistically significant (P = 0.995). For the concentration adjusted by tacrolimus daily dose (C/D), the mean value was highest in the IRRT group(29.76±23.46μg/ml/g) and lowest in the no-RRT group(5.46±6.80μg/ml/g), with significant differences among these groups (P < 0.0001) (Figure 1).

We examined renal function's impact on Cmin in patients not undergoing RRT. Using 212 plasma concentrations, we employed SCr and CRCL (Cockcroft-Gault equation) as renal function indices and assessed their effect on Cmin and C/D, creating scatter plots. Spearman’s correlation analysis revealed a significant positive correlation between SCr and both Cmin (r=0.1733, P=0.0115) and C/D (r=0.6114, P<0.0001). Conversely, CRCL showed a significant negative correlation with Cmin (r=-0.2244, P=0.0010) and C/D (r=-0.3680, P<0.0001). Refer to Figure 2 for details.

5. Analysis of independent factors influencing ganciclovir Cmin

Further multiple linear regression analysis of ganciclovir Cmin indicated correlations with disease type, HGB, SCr, and CRRT. Diabetic patients exhibited a 0.869 μg/ml decrease in ganciclovir Cmin compared to non-diabetics (P=0.001). Transplant patients had a 0.842 μg/ml reduction in Cmin compared to non-transplant patients (P=0.008). Each 1 g/L increase in HGB level resulted in a 0.011 μg/ml decrease in Cmin (P=0.034). Additionally, each 1 μmol/L increase in SCr corresponded to a 0.006 μg/ml increase in Cmin (P=0.000). Administration of CRRT increased ganciclovir Cmin by 0.967 μg/ml (P=0.000). Predictors of ganciclovir Cmin are detailed in Table 5.

The final multiple linear regression equation is as follows:

Cmin=2.188-0.869×DM-0.842×TP-0.011×HGB+0.006×SCr+0.967×CRRT

where, Cmin is the trough concentration. “DM= 1” if the patient has diabetes, otherwise “DM= 0” ; “TP= 1” if the patient has transplantion, otherwise “TP= 0” ; “CRRT= 1” if the patient has CRRT, otherwise “CRRT= 0”.

Table 5．The independent influencing factors of Cmin

Parameters	Estimate Coefficients	Std. Error	t	VIF	p
(Intercept)	2.188	0.497	4.403		0.000
Diabetes	-0.869	0.263	-3.300	1.023	0.001
Transplantation	-0.842	0.315	-2.672	1.070	0.008
Hemoglobin,g/L	-0.011	0.005	-2.133	1.023	0.034
SCr, μmol/L	0.006	0.001	4.541	1.108	0.000
CRRT	0.967	0.263	3.679	1.032	0.000
F		11.600
R2		0.174
Adjusted R2		0.159
p		0.000
Stepwise multiple linear regression was conducted with inclusion and exclusion criteria set at 0.05 and 0.10, respectively (N = 281). Scr denotes serum creatinine, and CRRT stands for continuous renal replacement therapy.

6. Ganciclovir TDM and hemocytopenia

Leukopenia, neutropenia,thrombocytopenia, and HGB reduction incidence rates were 59.73%, 66.44%, 57.72%, and 63.76%, respectively, as detailed in Table 6. A significant correlation existed between ganciclovir Cmin and HGB reduction (r=0.139, P=0.020). ROC curve analysis (Figure 3) indicated a threshold ganciclovir Cmin value of 0.985 μg/ml, with an AUC of 0.600 (95% CI, 0.533-0.667) (P=0.004). No significant correlation was found between ganciclovir Cmin and reductions in other blood cell counts.

Table 6.Statistics of related adverse reactions (n=149)

Toxicity	Cases（%）
Leukopenia	89（59.73）
White blood cell count＜3×10⁹/L	12（8.05）
Decrease in white blood cell count from baseline＞20%	75（50.34）
Neutropenia	99（66.44）
Neutrophil count＜1.5×10⁹/L	4（2.68）
Decrease in neutrophil count from baseline＞20%	82（55.03）
Thrombocytopenia	86（57.72）
Blood platelet count＜100×10⁹/L	34（22.82）
Decrease in platelet count from baseline＞50%	20（13.42）
Decreased hemoglobin	95（63.76）
Hemoglobin＜80g/L	53（35.57）
Decrease in hemoglobin from baseline＞20%	30（20.13)

7. Ganciclovir TDM and hepatic or renal adverse effects

No significant link was found between ganciclovir levels and liver function adverse reactions (ALT, AST, and TBIL), while a notable correlation existed between ganciclovir concentrations and elevated blood creatinine adverse reactions (r=0.134, P=0.025). ROC curve analysis revealed that the threshold ganciclovir Cmin value for adverse reactions with increased SCr was 0.995 μg/ml, with an area under the curve of 0.701 (95% CI, 0.612-0.789) (P=0.001).

The optimal ganciclovir exposure in adults and children is undefined. Nokta et al[23] showed that inhibition occurred at various concentrations. PK/PD studies have not confirmed whether ganciclovir is concentration- or time-dependent. Case studies[24–26] suggest TDM for optimizing ganciclovir regimens. Different centers have established specific target ranges for ganciclovir TDM[10, 20]. In our study, only 19.22% of patients with confirmed CMV lung infections achieved the target Cmin range of 2.0–4.0 µg/ml, with 70.82% below 2.0 µg/ml. Despite the low Cmin attainment rate, our CMV negativization rate was 68.46%, and overall treatment efficacy was 73.15%, indicating good clinical outcomes, similar to other studies[10, 22, 28]. The discrepancy between low Cmin attainment and high cure rates may be due to the pharmacological activity of the intracellular triphosphate form of ganciclovir[29], suggesting that current Cmin target ranges may be set too high.

CRRT increased ganciclovir Cmin, whereas IRRT had no significant effect. After dose adjustment, the highest concentrations were in intermittent dialysis patients. Galar et al. [22] found higher Cmin in hemodialysis patients without evaluating different modalities. Another study [20] in transplant patients showed lower ganciclovir Cmin in the IRRT group compared to the CRRT group, though not statistically significant. An earlier study [30] reported a single 4-hour dialysis session reduced plasma concentration by about 50%. Limited research on dialysis modalities suggests considering different hemodialysis durations when dosing ganciclovir. In patients not on renal replacement therapy, Cmin or C/D correlated significantly with renal function; better renal function meant lower ganciclovir exposure. Ganciclovir elimination depends entirely on renal function, with evidence [20] showing sub-target Cmins in patients with eGFR > 90 mL/min/1.73 m². These findings stress the need for further studies to optimize ganciclovir dose adjustments for patients with renal insufficiency.

Besides blood creatinine and CRRT, our study revealed that diabetes mellitus, organ transplantation, and HGB levels at the time of TDM also independently influence ganciclovir Cmin. Contrasting with a prior study [22] that found low eGFR, but not solid organ transplantation, to significantly impact Cmin, our findings differ possibly due to the predominance of lung transplantation (21/29, 72.41%) in our study compared to heart (10/26, 38.46%) and liver (11/26, 42.31%) transplants in the previous study. The effects of solid organ transplantation on ganciclovir Cmin require further research. The impact of underlying diseases and blood cells on ganciclovir Cmin also necessitates additional investigation. Our results suggest that the varying pathophysiological states in patients underscore the utility of TDM in understanding in vivo ganciclovir exposure.

This study, along with findings by Gatti et al. [28] and Ritchie et al. [13], found no significant correlation between ganciclovir Cmin and its efficacy in CMV eradication or clinical improvement, possibly due to wide variations in IC50 (0.1 to 1.7 mg/L) and IC90 (up to 3.5 mg/L) required for CMV replication reduction [28]. Binary logistic regression analysis revealed that prolonged ganciclovir use and higher patient albumin levels were favorable prognostic factors. A Dutch study [31] attributed the slow reduction in CMV viral load with standard dosing to inadequate dosing or poor immune status, suggesting that enhancing the patient's immune response and extending ganciclovir treatment under inadequate exposure conditions could promote viral clearance.

Ganciclovir TDM mitigates toxicity. Our study found significant correlation between ganciclovir Cmin and HGB reduction, with a 0.985 µg/ml threshold for HGB reduction, a novel finding. [20, 28]Clinical studies show varying results regarding ganciclovir Cmin and toxicity. Our findings necessitate further investigation. The adverse event thresholds were below our institution's target range for ganciclovir Cmin (2.0 vs. 4.0 µg/ml), with low actual Cmin compliance rate (19.22%) and high therapeutic efficacy (73.15%), suggesting high Cmin may be nonessential. Additional research should determine if lowering Cmin ensures efficacy and safety.

Our study found that ganciclovir Cmin significantly influenced the incidence of adverse reactions linked to elevated blood creatinine. ROC analysis determined a critical ganciclovir Cmin of 0.995 µg/ml associated with these adverse reactions. However, the link between ganciclovir and severe nephrotoxicity remains unclear, as no studies have confirmed a quantitative relationship between ganciclovir Cmin and nephrotoxicity occurrence. Only one study on pediatric hematopoietic cell transplant recipients [32] reported that intravenous ganciclovir was associated with severe renal dysfunction requiring renal replacement therapy.

The study has some limitations. Recent research indicates that AUC24h more accurately predicts clinical outcomes. Only ganciclovir Cmin was collected in our study without considering the AUC and peak concentrations because of retrospective data collection. Additionally, our study used the CT-based human cytomegalovirus nucleic acid assay, rather than the viral load in IU/mL as recommended by WHO guidelines.

This study on ganciclovir therapeutic drug monitoring found no link between ganciclovir Cmin and clinical efficacy; however, Cmin below the target range did not impact efficacy outcomes in our patients. For the first time, we identified Cmin thresholds associated with a decrease in HGB and an increase in blood creatinine levels, at 0.985 µg/ml and 0.995 µg/ml, respectively. Renal replacement therapy was observed to likely elevate ganciclovir Cmin, indicating the necessity for dosage adjustments based on renal function and therapy. These results underscore the importance of ganciclovir use in TDM.

Transparency declarations

None to declare.

Funding

This study was supported by the Fund of National High Level Hospital Clinical Research Funding-2023-NHLHCRF-YYPP-TS-03.

Author Contribution

Conceptualization, W.C. and D.G.; methodology, X.W.; soft-ware, D.G.; validation, W.C.; formal analysis, Y.S.; investigation, L.Z. , Y.C. ,and X.K.; data curation, P.L.; writing—original draft preparation, D.G.; writing—review and editing,W.C.; visuali zation, D.G.; supervision, W.C.; funding acquisition, W.C. All authors have read and agreed to the published version of the manuscript.

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No competing interests reported.

Efficacy and toxicity analysis of ganciclovir in patients with cytomegalovirus lung infection: what is new for target range of therapeutic drug monitoring

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