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Roeland Zoutendijk,
Hans L Zaaijer,
Theodora E M S de Vries-Sluijs,
Jurrien G P Reijnders,
Jan W Mulder,
Frank P Kroon, Clemens Richter,
Annemiek A van der Eijk,
Milan J Sonneveld,
Bettina E Hansen,
Robert A de Man,
Marchina E van der Ende,
Harry L A Janssen
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ABSTRACT: Background. The kinetics of hepatitis B surface antigen (HBsAg) are predictive in HBV-infected patients treated with pegylated interferon. Knowledge about the value of HBsAg levels in patients coinfected with HBV and human immunodeficiency virus (HIV) is lacking. Methods. We quantified serum HBsAg in a Dutch multicenter cohort of 104 patients coinfected with HIV and HBV who were treated with tenofovir disoproxil fumarate (TDF) as part of highly active antiretroviral therapy. The median duration of therapy was 57 months (interquartile range, 34-72 months). Results. Hepatitis B e antigen (HBeAg)-positive patients achieved a decline of 2.2 log IU/mL in HBsAg, whereas HBeAg-negative patients only achieved a decline of 0.6 log IU/mL during 6 years of TDF therapy. Declines in HBsAg at months 6 and 12 correlated with CD4 cell count for HBeAg-positive patients. Five HBeAg-positive patients (8%) and 3 HBeAg-negative patients (8%) cleared HBsAg. HBeAg-negative patients who cleared HBsAg had lower baseline HBsAg as compared to patients who remained HBsAg positive. The majority of patients who cleared HBsAg achieved this end point within the first year. In HBeAg-positive patients, decline in HBsAg at month 6 was predictive of achieving HBsAg seroclearance. Conclusions. Receipt of TDF therapy by HIV/HBV-coinfected patients for up to 6 years led to a significant decrease in HBsAg in the HBeAg-positive population. HBsAg kinetics early during treatment were predictive of HBsAg seroclearance and correlated with an increased CD4 cell count, underlining the importance of immune restoration in HBV clearance.
The Journal of Infectious Diseases 07/2012; 206(6):974-80. · 6.41 Impact Factor
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ABSTRACT: Several studies reported an association between immunodeficiency and non-AIDS-defining diseases. We investigated whether nonstructured treatment interruptions and episodes of viremia during suppressive combination antiretroviral therapy were independently associated with non-AIDS diseases.
Six thousand four hundred forty patients with viral suppression (<50 copies/mL) within 48 weeks of starting combination antiretroviral therapy were selected from the Dutch ATHENA cohort. In proportional hazards models, associations between treatment interruptions, viral suppression, low-level (50-400 copies/mL), and high-level viremia (>400), and serious non-AIDS diseases (cardiovascular disease, chronic renal failure, liver fibrosis/cirrhosis) were investigated by including time-updated cumulative exposure to either viremia and interruptions or HIV RNA >400 copies per milliliter.
During 24,603 person-years, of which 88.5% occurred during viral suppression, 102 patients developed cardiovascular disease, 54 chronic renal failure, and 70 liver fibrosis/cirrhosis. Overall incidence of non-AIDS diseases ranged from 1.41 (95% confidence interval: 0.73 to 2.46) per 100 person-years for CD4 counts <200 to 0.71 (0.49 to 1.00) for CD4 ≥500 cells per cubic millimeter. Compared with viral suppression, high-level viremia was associated only with cardiovascular disease (relative hazard: 1.37, 1.04 to 1.81 per year longer), whereas interruptions and low-level viremia were not associated with non-AIDS diseases. Relative hazards for cumulative exposure to RNA >400 versus ≤400 copies per milliliter were 1.32 (1.01 to 1.73) for cardiovascular disease, 1.13 (0.66 to 1.92) for renal failure, and 0.86 (0.51 to 1.44) for fibrosis/cirrhosis.
Lower CD4 counts are associated with increased risk of non-AIDS diseases, whereas high-level viremia seems to be independently associated with cardiovascular disease. However, the power to detect associations with viremia or interruptions may have been limited as most events occurred during viral suppression.
JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2012; 60(3):265-72. · 4.43 Impact Factor
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ABSTRACT: Ribavirin is an essential component in the treatment of chronic hepatitis C (HCV) infection. Although ribavirin dose is weight-based, data in the literature suggest large between-patient variability in plasma ribavirin concentrations. Recent studies indicate that higher ribavirin exposure results in higher sustained viral response rates. Monitoring ribavirin concentration is suggested in the literature, but it is unclear at what time point during treatment plasma ribavirin concentrations should be monitored.
To investigate the association between early plasma ribavirin concentrations and ribavirin dosing with steady-state (Css) concentration and the between- and within-patient variability in plasma ribavirin concentration in clinical practice.
We performed a prospective observational cohort study in patients with HCV who received pegylated interferon in combination with oral weight-based ribavirin (12-15 mg/kg) twice daily. Trough plasma ribavirin concentrations at Weeks 1, 2, 4, 8, 12, 16, 20, and 24 were studied using a validated high-performance liquid chromatography assay.
In total, 53 patients (37 male, 16 female) with a mean age of 51 years (range, 26-68 years) were included and 209 samples were collected. There was a significant correlation between Week 2 as well as Week 4 and plasma ribavirin Css (r = 0.589 and r = 0.714, P < 0.05, respectively). Ribavirin Css was reached at Week 8 of HCV treatment. There was no correlation between dose in mg/kg and Css (r = 0.181, P = 0.263). The between- and within-patient coefficients of variation of plasma ribavirin concentrations at Week 8 and beyond were 43% and 13%, respectively.
In HCV-infected patients, ribavirin steady-state concentrations can be predicted by measurement of concentrations made early after the start of therapy.
Therapeutic drug monitoring 02/2011; 33(1):40-4. · 2.43 Impact Factor
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ABSTRACT: Therapeutic drug monitoring (TDM) is recommended in several international HIV treatment guidelines. The adherence of clinicians to these recommendations is unknown. The authors evaluated the adherence to the Dutch TDM guideline of 2005.
From the ATHENA cohort study, three scenarios were selected for which the guideline recommended TDM: 1) start of a combination of lopinavir/ritonavir + efavirenz or nevirapine (drug-drug interaction); 2) start of efavirenz (routine TDM); and 3) use of nelfinavir during pregnancy. For each scenario, we determined the proportion of patients for whom TDM was performed. Multivariable logistic regression modeling was used to identify determinants for the use of TDM.
The adherence to the TDM guideline was 46.7% in patients who started lopinavir/ritonavir plus efavirenz or nevirapine; 9.5% for patients who started efavirenz; and 58.5% for patients who used nelfinavir during pregnancy. Patients treated in clinics that had a TDM assay available locally and patients treated in academic clinics were more likely to receive TDM. A higher baseline HIV viral load was another significant predictor for the performing TDM.
The adherence of clinicians to the Dutch TDM guidelines varied from low to moderate for the three investigated TDM scenarios. This study identifies several determinants for the use of TDM, which may be useful information for those responsible for generating TDM guidelines.
Therapeutic drug monitoring 02/2011; 33(1):32-9. · 2.43 Impact Factor
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Theodora E M S de Vries-Sluijs,
Jurriën G P Reijnders,
Bettina E Hansen,
Hans L Zaaijer,
Jan M Prins,
Suzan D Pas,
Martin Schutten,
Andy I M Hoepelman, Clemens Richter,
Jan W Mulder,
Rob A de Man,
Harry L A Janssen,
Marchina E van der Ende
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ABSTRACT: We investigated the long-term efficacy and renal safety of tenofovir disoproxil fumarate (TDF), administered to patients co-infected with human immunodeficiency virus and hepatitis B virus (HBV) as part of an antiretroviral therapy.
We performed a multicenter, prospective cohort study of 102 patients co-infected with human immunodeficiency virus and HBV who were treated with TDF.
At baseline, 80% of patients had a detectable viral load (HBV DNA >20 IU/mL). Among patients positive for hepatitis B e antigen (HBeAg) (n = 67), 92% had a virologic response (HBV DNA <20 IU/mL) after 5 years of treatment. There was no difference between patients with or without lamivudine resistance at baseline (P = .39). Loss rates of HBeAg and hepatitis B s antigen (HBsAg) were 46% and 12%, respectively. Among HBeAg-negative patients (n = 15), 100% had a virologic response after 4 years of treatment and 2 (13%) lost HBsAg. Twenty subjects (20%, all HBeAg-negative) had undetectable HBV DNA at baseline; during a median follow-up period of 52 months (interquartile range, 41-63 mo), 19 (95%) maintained a virologic response and 2 (10%) lost HBsAg. Overall, one patient acquired a combination of resistance mutations for anti-HBV drugs and experienced a virologic breakthrough. Three (3%) patients discontinued TDF because of increased serum creatinine levels. The estimated decrease in renal function after 5 years of TDF therapy was 9.8 mL/min/1.73 m(2), which was most pronounced shortly after TDF therapy was initiated.
TDF, administered as part of antiretroviral therapy, is a potent anti-HBV agent with a good resistance profile throughout 5 years of therapy. Only small nonprogressive decreases in renal function were observed.
Gastroenterology 12/2010; 139(6):1934-41. · 11.68 Impact Factor
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Herman G Sprenger,
Nienke Langebeek,
Paul G H Mulder,
Chris H H Ten Napel,
Robert Vriesendorp,
Andy I M Hoepelman,
Jean-Claude Legrand,
Peter P Koopmans,
Marjo E E Van Kasteren,
Bert Bravenboer,
Reinier W Ten Kate,
Paul H P Groeneveld,
Tjip S van der Werf,
Elisabeth H Gisolf, Clemens Richter
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ABSTRACT: Maintenance with a triple nucleoside reverse transcriptase Inhibitor (NRTI) regimen after successful induction with a dual NRTI/protease inhibitor (PI) combination may be advantageous, because of low pill burden, favorable lipids, and less drug interactions. This strategy to become free of PI-related problems without losing viral efficacy has not been formally tested. We performed a randomized, open-label, multicenter, 96-week comparative study in antiretroviral therapy (ART)-naïve patients with CD4 <or=350 cells/mm(3) and HIV-1 RNA concentrations (viral load [VL]) greater than 30,000 copies per milliliter. Patients were randomized after reaching VL less than 50 copies per milliliter on two consecutive occasions between 12 and 24 weeks after start of zidovudine/lamuvidine and lopinavir/ritonavir combination. Eligible subjects switched to abacavir/lamivudine/zidovudine (TZV) or continued the PI-containing regimen. Here we present the 48-week data with virologic success rate (failure: VL > 50 copies per milliliter). Two hundred seven patients had similar baseline (BL) characteristics: median CD4 180 cells/mm(3), median VL 5.19 log(10) copies per milliliter. One hundred twenty subjects (58%) met randomization criteria. Baseline VL differed significantly between dropouts and randomized subjects (median 5.41 versus 5.06 log(10) copies per milliliter, p = 0.017), as did CD4 cells (median 160 and 200 cells/mm(3), p = 0.044). Sixty-one subjects received TZV and 59 subjects continued NRTIs/PI. At week 48, 2 patients in the TZV group and 5 in the PI group did not have a sustained virologic suppression (log rank test; p = 0.379). CD4 counts increased significantly in both arms. In ART-naïve patients, TZV maintenance had similar antiviral efficacy compared to continued standard ART at 48 weeks after baseline. Patients on successful standard ART can be safely switched to a NRTI-only regimen, at least for the tested time period.
AIDS patient care and STDs 06/2010; 24(6):361-6. · 2.68 Impact Factor
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Matthijs van Luin,
Marchina E Van der Ende, Clemens Richter,
Mirjam Visser,
Diari Faraj,
Andre Van der Ven,
Luc Gelinck,
Frank Kroon,
Ferdinand W Wit,
Ron H N Van Schaik,
Paul F M Kuks,
David M Burger
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ABSTRACT: HIV-infected travellers frequently use atovaquone/proguanil as malaria prophylaxis. We compared atovaquone/proguanil pharmacokinetics between healthy volunteers and HIV-infected patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. The geometric mean ratio (95% confidence interval) area under the curve (AUC)0-->t for atovaquone relative to the healthy volunteers was 0.25 (0.16-0.38), 0.26 (0.17-0.41) and 0.54 (0.35-0.83) for patients on efavirenz, lopinavir/ritonavir and atazanavir/ritonavir, respectively. Proguanil plasma concentrations were also significantly lower (38-43%). Physicians should be alert for atovaquone/proguanil prophylaxis failures in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir.
AIDS (London, England) 03/2010; 24(8):1223-6. · 4.91 Impact Factor
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European journal of obstetrics, gynecology, and reproductive biology 09/2009; 147(2):236-7. · 1.97 Impact Factor
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ABSTRACT: To establish whether efavirenz dose reduction in patients with high plasma concentrations prevents toxicity-induced efavirenz discontinuations.
HIV-infected patients with a high efavirenz plasma concentration (>or=4.0 mg/L) while using efavirenz 600 mg once daily as part of their highly active antiretroviral therapy regimen were selected from the AIDS Therapy Evaluation in The Netherlands cohort study. These patients were classified into 2 groups. The reduced-dose group contained all patients who underwent dose reduction after the high plasma concentration measurement; the standard-dose group consisted of patients who had no dose reduction. Kaplan-Meier and Cox proportional hazards analysis were used to assess the impact of dose reduction on toxicity-induced efavirenz discontinuations.
One hundred eighty patients with high plasma efavirenz levels were included, 47 of them subsequently had their efavirenz dose reduced from 600 mg to 400 mg once-daily, which resulted in a 41% decrease in the median efavirenz plasma concentration. At week 48, the Kaplan-Meier estimated cumulative incidence of toxicity-induced efavirenz discontinuations was 11.5% in patients who continued the standard dose versus 2.3% in patients who had a dose reduction; P = 0.066 (log-rank test). Dose reduction was not associated with loss of virological suppression.
Dose reduction may prevent toxicity-induced discontinuations in patients with high efavirenz plasma concentrations, whereas not compromising virological efficacy.
JAIDS Journal of Acquired Immune Deficiency Syndromes 07/2009; 52(2):240-5. · 4.43 Impact Factor
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American Journal of Kidney Diseases 04/2009; 53(3):xxxv-xxxvii. · 5.43 Impact Factor
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Jasper van der Lugt,
Angela Colbers,
Jose Molto,
David Hawkins,
Marchina van der Ende,
Martin Vogel,
Christoph Wyen,
Malte Schutz,
Peter Koopmans,
Kiat Ruxrungtham, Clemens Richter,
David Burger
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ABSTRACT: Pregnancy affects the pharmacokinetics of most protease inhibitors. Saquinavir, when administered in a tablet formulation, has not been studied extensively in this setting.
A pharmacokinetic, prospective, multicentre trial of HIV type-1-infected pregnant women treated with saquinavir (500 mg tablets) boosted with ritonavir at a dose of 1,000/100 mg twice daily plus a nucleoside backbone was conducted. Pharmacokinetic curves were recorded for 12 h in the second trimester (week 20 +/-2), the third trimester (week 33 +/-2) and post-partum (weeks 4-6). Blood was sampled pre-dosing and at 1, 2, 3, 4, 6, 8, 10 and 12 h post-dosing. Pharmacokinetic parameters were calculated using WinNonlin software version 4.1.
A total of 37 women were included in the analysis. Mean (+/-sd) values for saquinavir area under the curve (AUC(0-12h)) were 23.47 h*mg/l (11.92) at week 20 (n=16), 23.65 h*mg/l (9.07) at week 33 (n=31) and 25.00 h*mg/l (11.81) post-partum (n=9). There was no significant difference in the saquinavir AUC(0-12h) when comparing the data during pregnancy and post-partum. Subtherapeutic plasma concentrations of saquinavir (defined as <0.10 mg/l) were not observed throughout the study. No major safety concerns were noted.
Saquinavir exposure in the new tablet formulation generates adequate saquinavir concentrations throughout the course of pregnancy and is safe to use; therefore, no dose adjustment during pregnancy is needed.
Antiviral therapy 01/2009; 14(3):443-50. · 3.16 Impact Factor
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ABSTRACT: Recommendations that nevirapine (NVP) should be avoided in female individuals with CD4 cell counts >250 cells/microL and in male individuals with CD4 cell counts >400 cells/microL are based on findings in treatment-naive patients. It is unclear whether these guidelines also apply to treatment-experienced patients switching to NVP-based combination therapy.
Patients in the ATHENA cohort study who had used NVP-based combination therapy were included. We identified patients who discontinued NVP-based combination therapy because of hypersensitivity reactions (HSRs; rash and/or hepatotoxicity) within 18 weeks after starting such therapy. We grouped patients according to their CD4 cell count at the start of NVP-based combination therapy (current CD4 cell count) as having a high CD4 cell count (for female patients, >250 cells/microL; for male patients, >400 cells/microL) or a low CD4 cell count. Treatment-experienced patients were further subdivided according to the last available CD4 cell count before first receipt of antiretroviral therapy (ART; pre-ART CD4 cell count) using the same criteria. Risk factors for HSR were assessed using multivariate logistic regression.
Of 3752 patients receiving NVP-based combination therapy, 231 patients (6.2%) discontinued NVP therapy because of HSRs. Independent risk factors included female sex and Asian ethnicity. Having an undetectable viral load (VL) at the start of NVP therapy was associated with reduced risk of developing an HSR (adjusted odds ratio [OR], 0.52; 95% confidence interval [CI], 0.38-0.71). Pretreated patients with low pre-ART and high current CD4 cell counts and a detectable VL when switching to NVP-based combination therapy had a significantly higher risk of developing an HSR, compared with treatment-naive patients who started NVP therapy with low CD4 cell counts (adjusted OR, 1.87; 95% CI, 1.11-3.12); pretreated patients with low pre-ART CD4 cell counts who switched to NVP therapy with a high current CD4 cell count and an undetectable VL did not have an increased risk of developing an HSR (adjusted OR, 1.03; 95% CI, 0.66-1.61).
Treatment-experienced patients who start NVP-based combination therapy with low pre-ART and high current CD4 cell counts and an undetectable VL have a similar likelihood for discontinuing NVP therapy because of HSRs, compared with treatment-naive patients with low CD4 cell counts. This suggests that NVP-based combination therapy may be safely initiated in such patients. However, in similar patients with a detectable VL, it is prudent to continue to adhere to current CD4 cell count thresholds.
Clinical Infectious Diseases 03/2008; 46(6):933-40. · 9.15 Impact Factor
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ABSTRACT: We conducted a prospective study to update our knowledge of fever of unknown origin (FUO) and to explore the utility of a structured diagnostic protocol. From December 2003 to July 2005, 73 patients with FUO were recruited from 1 university hospital (n = 40) and 5 community hospitals (n = 33) in the same region in The Netherlands. FUO was defined as a febrile illness of >3 weeks' duration, a temperature of >38.3 degrees C on several occasions, without a diagnosis after standardized history-taking, physical examination, and certain obligatory investigations. Immunocompromised patients were excluded. A structured diagnostic protocol was used. Patients from the university hospital were characterized by more secondary referrals and a higher percentage of periodic fever than those referred to community hospitals. Infection was the cause in 16%, a neoplasm in 7%, noninfectious inflammatory diseases in 22%, miscellaneous causes in 4%, and in 51%, the cause of fever was not found (no differences between university and community hospitals). There were no differences regarding the number and type of investigations between university and community hospitals. Significant predictors for reaching a diagnosis included continuous fever; fever present for <180 days; elevated erythrocyte sedimentation rate, C-reactive protein, or lactate dehydrogenase; leukopenia; thrombocytosis; abnormal chest computed tomography (CT); and abnormal F-fluorodeoxyglucose positron emission tomography (FDG-PET). For future FUO studies, inclusion of outpatients and the use of a set of obligated investigations instead of a time-related criterion are recommended. Except for tests from the obligatory part of our protocol and cryoglobulins in an early stage, followed by FDG-PET, and in a later stage by abdominal and chest CT, temporal artery biopsy in patients aged 55 years or older, and possibly bone marrow biopsy, other tests should not be used as screening investigations.
Medicine 02/2007; 86(1):26-38. · 4.35 Impact Factor
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David Burger,
Ilse van der Heiden,
Charles la Porte,
Marchina van der Ende,
Paul Groeneveld, Clemens Richter,
Peter Koopmans,
Frank Kroon,
Herman Sprenger,
Jan Lindemans,
Paul Schenk,
Ron van Schaik
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ABSTRACT: To characterize the demographic and pharmacogenetic factors that influence interpatient variability in the plasma concentrations of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz.
Data from all samples analyzed for efavirenz in our TDM service in 2002 and 2003 were reviewed. Information on gender, age, body weight, height, race, hormonal contraceptive use (in a subset of patients), and time between sampling and last intake was recorded. PCR-restriction fragment length polymorphism analysis was performed to detect the cytochrome P450 2B6 (CYP2B6) C1459T variant (present in CYP2B6*6 and CYP2B6*7) which is associated with low CYP2B6 activity.
A total of 255 patients were included in this analysis. The median plasma efavirenz concentration was 2.50 (interquartile range: 1.85-3.55) mg l(-1). Eight patients (3.1%) were considered to have a subtherapeutic plasma concentration (<1.0 mg l(-1)) and 48 (18.9%) a toxic efavirenz concentration (>4.0 mg l(-1)). Gender, time after last intake, and race were the only factors that were significantly related to plasma efavirenz concentration in a multivariate analysis. No influence was observed for body weight, hormonal contraceptive use, and the presence of the CYP2B6 C1459T polymorphism.
Gender and race are important factors in determining interpatient variability in plasma efavirenz concentrations which were unaffected by the presence of the CYP2B6 C1459T polymorphism. Physicians should be particularly alert for signs of efavirenz-induced toxicity in females and non-Caucasian patients.
British Journal of Clinical Pharmacology 02/2006; 61(2):148-54. · 2.96 Impact Factor
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David Burger,
Patricia Hugen,
Peter Reiss,
Inge Gyssens,
Margriet Schneider,
Frank Kroon,
Gerrit Schreij,
Kees Brinkman, Clemens Richter,
Jan Prins,
Rob Aarnoutse,
Joep Lange
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ABSTRACT: Both virological failure and the toxicity of HIV protease inhibitors have been related to interindividual variability of plasma drug concentrations. Therapeutic drug monitoring (TDM) offers the possibility to detect patients with drug concentrations outside therapeutic ranges, who can subsequently benefit from dose modifications.
ATHENA was a randomized controlled clinical trial. Subjects were randomly assigned to either a TDM group, in which the results of drug concentration measurements plus advice were reported to their treating physician, or to a control group for whom TDM results were not reported. This analysis refers to treatment-naive patients who started a regimen containing indinavir or nelfinavir before November 1999.
A total of 147 patients were randomly assigned: 92 to nelfinavir, 55 to indinavir. After one year of follow-up significantly fewer patients in the TDM group had discontinued nelfinavir or indinavir than in the control group: 17.4 versus 39.7%. This was mainly driven by a significantly lower rate of discontinuation because of virological failure in nelfinavir patients: 2.4% in the TDM group versus 17.6% in the control group, and by a non-significant difference in the rate of discontinuation because of toxicity in indinavir patients: 14.3% in the TDM group versus 29.6% in the control group. In a non-completer equals failure analysis of all randomized patients, the TDM group showed a significantly higher proportion of patients with a viral load below 500 copies after 12 months of treatment (78.2 versus 55.1%).
TDM of nelfinavir and indinavir in treatment-naive patients improves treatment response.
AIDS 06/2003; 17(8):1157-65. · 6.24 Impact Factor
