C. Wyen - Academia.edu (original) (raw)
Papers by C. Wyen
Journal of Clinical Virology, 2006
Background: Disease progression in HIV infection has been associated with switch of viral corecep... more Background: Disease progression in HIV infection has been associated with switch of viral coreceptor usage from CCR5 to CXCR4. Objectives: To investigate the relationship between HIV-coreceptor tropism and clinical and virological outcome in 40 heavily pretreated patients over time. Methods: Coreceptor phenotype was predicted after sequencing the V3 loop of the HIV glycoprotein 120. Results: Coreceptor use was stable during observation time in 87% of patients, and CCR5 tropism was predominant. Viral mutations in the pol gene and clinical parameters were not predictive for coreceptor switching. Conclusions: Even in patients with repeated HAART failure, CCR5 antagonists might be a valuable treatment option.
Clinical Infectious Diseases, 2020
Background Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug... more Background Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus. Methods Antiretroviral treatment–experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012–1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression. Results Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years [interquartile range, 46.7–59.0] vs 47.7 [39.7–54.3]), and a higher proportion had ≥1 ...
HIV Medicine, 2020
Non‐treponemal serological tests are used to monitor treatment response during syphilis infection... more Non‐treponemal serological tests are used to monitor treatment response during syphilis infection. Syphilis‐ and HIV‐coinfected patients may experience incomplete resolution in non‐treponemal titres, which is referred to as the serofast state. The goal of this study was to evaluate risk factors for serofast state in HIV‐infected patients.
AIDS, 2019
Parameter estimates for trends and patterns of excess mortality among persons on antiretroviral t... more Parameter estimates for trends and patterns of excess mortality among persons on antiretroviral therapy in high-income European settings. AIDS, 33, S271-S281.
Blood, 2018
Introduction: Human immunodeficiency virus (HIV)-associated primary effusion lymphoma (PEL) is a ... more Introduction: Human immunodeficiency virus (HIV)-associated primary effusion lymphoma (PEL) is a rare and aggressive subtype of B-cell Non-Hodgkin lymphomas (NHL). PEL usually arises in body cavities such as the peritoneum, the pleural space, and pericardium, but may also present as extracavitary lesions without effusion. Definitive diagnosis hinges on detection of viral infection by human herpes virus 8 (HHV-8) in the neoplastic cells. Optimal treatment for HIV-PEL has not been defined. The aim of the present study was to analyze clinical characteristics, treatment and outcome of pts with HIV-PEL who were included in the German HIV-related lymphoma cohort study. Methods: The German HIV-related lymphoma cohort study is a prospective multicenter study that includes adult HIV-1 infected pts with biopsy or cytologically proven HIV-related lymphoma. Patients were diagnosed at 32 participating centers in Germany and Austria since January 2005. Data on HIV-infection and lymphoma character...
HIV Medicine, 2016
Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor (INSTI), is now among... more Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor (INSTI), is now among the most frequently used antiretroviral agents. However, recent reports have raised concerns about potential neurotoxicity. Methods We performed a retrospective analysis of a cohort of HIV-infected patients who had initiated an INSTI in two large German outpatient clinics between 2007 and 2016. We compared discontinuation rates because of adverse events (AEs) within 2 years of starting treatment with dolutegravir, raltegravir or elvitegravir/cobicistat. We also evaluated factors associated with dolutegravir discontinuation. Results A total of 1950 INSTI-based therapies were initiated in 1704 patients eligible for analysis within the observation period. The estimated rates of any AE and of neuropsychiatric AEs leading to discontinuation within 12 months were 7.6% and 5.6%, respectively, for dolutegravir (n = 985), 7.6% and 0.7%, respectively, for elvitegravir (n = 287), and 3.3% and 1.9%, respectively, for raltegravir (n = 678). Neuropsychiatric AEs leading to dolutegravir discontinuation were observed more frequently in women [hazard ratio (HR) 2.64; 95% confidence interval (CI) 1.23-5.65; P = 0.012], in patients older than 60 years (HR: 2.86; 95% CI: 1.42-5.77; P = 0.003) and in human leucocyte antigen (HLA)-B*5701-negative patients who initiated abacavir at the same time (HR: 2.42; 95% CI: 1.38-4.24; P = 0.002). Conclusions In this large cohort, the rate of discontinuation of dolutegravir because of neuropsychiatric adverse events was significantly higher than for other INSTIs, at almost 6% within 12 months. Despite the limitations of this retrospective study, the almost threefold higher discontinuation rates observed amongst women and older patients underscore the need for further investigation, especially in patient populations usually underrepresented in clinical trials.
HIV Medicine, 2017
We thank Capetti and colleagues for their interesting comments [1] which suggest that morning dos... more We thank Capetti and colleagues for their interesting comments [1] which suggest that morning dosing may help resolve dolutegravir (DTG)-related insomnia and sleep disorders. In our retrospective study [2], we had no information on the timing of DTG administration in most of our patients. However, in our experience, patterns of adverse events leading to DTG discontinuation were heterogeneous and not limited to sleep disorders. They included dizziness, depression, headache, paraesthaesia, poor concentration and slow thinking. Although relatively rare, reversible and usually mild to moderate, these events were less frequently seen with elvitegravir or raltegravir. Since our initial publication, we have seen additional patients complaining of dizziness or cognitive problems 1-2 h after DTG intake, suggesting that peak plasma levels may be too high in these individuals. Other groups from the Netherlands [3], Italy [4,5] and France [6] have also reported unexpected adverse events with DTG. These include anxiety, irritability and depression but also headache and musculoskeletal pain. In these patients, it seems unlikely that a switch to morning dosing would resolve neuropsychiatric symptoms. Of note, Capetti and colleagues have confirmed our observations that neuropsychiatric events were more frequent in older and in female patients, suggesting a pharmacokinetic problem. Indeed, recent pharmacokinetic studies have found higher drug exposure in older patients [7,8] but also in patients treated with atazanavir or cobicistat [9,10]. We believe that there is an urgent need for more data on drug levels in these patient populations, especially in individuals who develop neuropsychiatric events. Capetti and colleagues' univariate analysis did not find a higher event rate with abacavir use. This is in contrast to our findings and those of other studies [3,4] and it is debatable whether currently available data are sufficient to exclude a drugÀdrug interaction between abacavir and DTG [11,12].
Journal of Clinical Oncology, 2011
8044 Background: No data are available on using PET-scans in HIV-HL. The goal of the present stud... more 8044 Background: No data are available on using PET-scans in HIV-HL. The goal of the present study is to analyse consecutive patients (pts) with HIV-HL who had at least one PET scan conducted during their course of primary chemotherapy (CT). METHODS In the German prospective multicenter trial pts. with HIV-HL are planned to receive 2x ABVD + 30 Gy involved field (IF) radiation (RT) for early stage (ES) favourable HL (stage I/II without risk factors), 4x BEACOPP baseline or 4x ABVD + 30 Gy IF for ES unfavourable HL, and 6-8 x BEACOPP baseline for advanced stage HL with BEACOPP being replaced by ABVD in pts with far advanced HIV-infection or poor performance status. Since the role of PET-scans is not specifically addressed in this trial FDG-PET is not routinely scheduled. However, as PET-scans are being performed on physician's choice we retrospectively analyzed results and clinical impact of FDG-PET in this cohort of pts. RESULTS From 03/04 to 12/10 105 pts (median age 43.9 yrs, 8 females) were included in the trial. 23 pts (22%) had ES favourable HL, 14 (13%) ES unfavourable HL, and 68 (65%) advanced stage HL. 26 of 105 pts had a total of 37 PET/PET-CT scans done at some point during their course of treatment. FDG-PET was conducted as part of the initial staging and for response assessment in 8 and 28 cases, respectively. 1 pt had a PET-scan performed to rule out a late relapse of HL or a second malignancy. A negative FDG-PET had an impact on further management in 15 pts with additional RT being omitted in 9 pts and CT for advanced HL being terminated after 6 or 7 cycles of BEACOPP in 5 pts and 1 pt, respectively. A PET-scan performed after 2 cycles of ABVD (PET2) proved negative (neg) in 3/3 pts with 2 of those not receiving IF-RT. PET4 proved negative in 4 of 5 pts with ES-unfavourable HL with IF-RT not being given in all PET4 neg. pts. All PET2/PET4 neg. pts who did not receive IF-RT (n=6) remain disease-free after a median follow-up of 24 months. RT was also successfully omitted in 3 pts with neg. FDG-PET after 6 or 8 cycles of CT. CONCLUSIONS Given the high negative predictive value of FDG-PET in HIV-negative HL, these preliminary data suggest that in pts with HIV-HL a negative PET-scan conducted after 2, 4 or 6-8 cycles of CT may allow the omission of IF-RT.
Clinical Pharmacology & Therapeutics, 2005
Background/Aims: The HIV protease inhibitors ritonavir and lopinavir both are substrates, inhibit... more Background/Aims: The HIV protease inhibitors ritonavir and lopinavir both are substrates, inhibitors, and (weak) inducers of cytochrome P450 3A4 (CYP3A4) in humans. The present study was conducted to quantify the changes of intestinal and hepatic CYP3A4 activity caused by combined therapeutic administration of the two drugs in HIV infected patients.Methods: In this open, two-period trial, midazolam (MID, 1.5 mg orally followed by 1.0 mg i.v. 4h later) was administered to 30 treatment-naïve HIV positive patients before and at least 14 days after the start of an antiretroviral regimen containing 400 mg lopinavir / 100 mg ritonavir (Kaletra®) bid. Plasma concentrations of MID and 1'-OH-midazolam (OHM) were analyzed up to 12h after the oral dose using LC-MS/MS (limit of quantification, LOQ, 0.2 ng/mL for both analytes).Results: Hepatic CYP3A4 activity, measured as hepatic MID clearance, was reduced from 71.9 l/h (CV, 34 %) to 25.5 l/h (CV, 69 %, given are geometric means (geometric CVs)). Intestinal CYP3A4 activity, measured as intestinal MID extraction, was reduced from 0.43 (CV, 31 %) to 0.09 (CV, 60 %). OHM formation fell below LOQ in all patients when Kaletra® was taken in, and the apparent half-life increased from 1.2h (CV, 23 %) to 2.6h (CV, 49 %).Conclusions: Both intestinal and hepatic CYP3A4 are pronouncedly inhibited by ritonavir / lopinavir suggesting that drugs metabolized by CYP3A4 should be dosed very cautiously in these patients.
Scandinavian Journal of Infectious Diseases, 2013
Background: Lung cancer is one of the most common Non-AIDS-defining malignancies in HIV-infected ... more Background: Lung cancer is one of the most common Non-AIDS-defining malignancies in HIV-infected patients. However, data on clinical outcome and prognostic factors is scarce. Methods: National, multicenter, retrospective cohort analysis of all cases of lung cancer seen in HIV-infected individuals from 2000 through 2010. Survival was analyzed with respect to the use of antiretroviral therapy (ART), specific lung cancer therapies and other potential prognostic factors. Results: A total number of 72 patients (mean age 55.5 years, CD4 T-cells 383/μl) were evaluated in this analysis. At time of lung cancer diagnosis, 86% were on antiretroviral therapy. Of these, 79% had undetectable HIV-1-RNA (<50copies/ml) for a mean duration of 4.0 years. All but one patient were current or former heavy smokers (mean: 42 package years). Median estimated overall survival was 1.08 years with a two-year-overall survival of 24 %. Prognosis did not improve during observation time. A limited lung cancer stage of I-IIIA was associated with better overall survival, when compared with the advanced stages IIIb/IV (p=0.0003). Other factors predictive for improved overall survival were better performance status, CD4 T-cells > 200/μl and a non intravenous drug use transmission risk for HIV. Conclusions: Currently, most cases of lung cancer occur in the setting of limited immune deficiency and a long-lasting viral suppression. As in HIV negative cases, clinical stage of lung cancer is highly predictive and long-term overall survival can only be achieved in limited stages. The still high mortality underscores the importance of smoking cessation strategies in HIV-infected patients.
Journal of Infection, 2007
Lymphomatoid granulomatosis (LYG) is a rare systematic lymphoproliferative disorder of uncertain ... more Lymphomatoid granulomatosis (LYG) is a rare systematic lymphoproliferative disorder of uncertain etiology. We present a rare case of isolated cerebral LYG developing in an HIV-1-infected patient after initiation of highly active antiretroviral therapy (HAART).
Journal of Antimicrobial Chemotherapy, 2009
Objectives: An increased risk of drug-related liver injury has been repeatedly reported in indivi... more Objectives: An increased risk of drug-related liver injury has been repeatedly reported in individuals infected with hepatitis C virus (HCV) receiving the antiretroviral drug nevirapine. This study was undertaken to assess the differences in the pharmacokinetics of nevirapine between patients with HIV/HCV coinfection and HIV infection that could explain higher rates of hepatotoxicity. Methods: A 12 h pharmacokinetic analysis was performed in 18 patients: 7 HIV/HCV-coinfected and 11 HIV-monoinfected. Advanced liver disease was an exclusion criterion in order to assess the impact of chronic HCV infection alone. Results: Comparing the two groups, no difference was observed between minimum and maximum drug levels or total drug exposure in terms of area under the curve. Conclusions: Hepatitis C coinfection does not alter the pharmacokinetics of nevirapine in patients with preserved liver function.
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2004
To describe the clinical course and risk factors of death in highly active antiretroviral therapy... more To describe the clinical course and risk factors of death in highly active antiretroviral therapy (HAART)-treated patients with progressive multifocal leukencephalopathy (PML); to evaluate the efficacy of cidofovir in addition to HAART. Retrospective multicenter cohort study of PML in HIV-1-infected patients. Diagnosis of PML was confirmed by histology or by positive polymerase chain reaction for JC virus (JCV) in cerebrospinal fluid (CSF) or was made by typical radiologic and clinical findings. Thirty-five cases of PML were identified. The diagnosis was made by histology (9 cases), detection of JCV in CSF (17 cases), and by radiologic findings (9 cases). Upon manifestation of PML, 15/35 patients had never received HAART, and 11/35 were on HAART for &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;6 months (median 1126 days). In 9/35 cases, clinical manifestation of PML occurred within 6 months after initiation of HAART. All patients received HAART after PML diagnosis. After a median follow-up of 553 days (range 28-2694 days), the median survival time was not reached. In 12 patients who were treated concomitantly with cidofovir, cumulative survival was significantly shorter than in patients without cidofovir (P = 0.03). Patients in whom PML was diagnosed while on HAART demonstrated a trend toward a shorter survival than HAART-naive patients (P = 0.15). PML continues to occur in HIV-1-infected patients even when they are treated with HAART. Patients developing PML on HAART had a trend toward a shorter median survival compared with treatment-naive patients, and cidofovir therapy was not associated with improved survival in this cohort.
Infection, 2006
Since the introduction of HAART, the clinical importance of hepatitis virus infection and its com... more Since the introduction of HAART, the clinical importance of hepatitis virus infection and its complications in human immunodeficiency virus (HIV)-infected persons have continuously grown. Coinfection with hepatitis B virus (HBV) and HIV is one of the leading causes of morbidity and mortality. To date, neither the optimal time point for initiation of anti-HBV therapy nor the best therapeutic approach has been clearly defined. We report the case of a 22-year-old African woman infected with HBV-and HIV-1 coinfection and severe impairment of liver function. HAART including lamivudine and tenofovir was started. Three weeks later, the patient achieved not only a restoration of her clinical situation and liver function, but she also demonstrated a complete suppression of both viruses. This impressive clinical course might be explained by the application of antiviral combination therapy including lamivudine and tenofovir. Tenofovir has shown a higher activity against HBV than other drugs. In addition, combination therapy for chronic hepatitis B might be more effective than monotherapy. Future studies need to clarify the value of combination treatment for patients with chronic hepatitis B.
HIV Medicine, 2005
Treatment of AIDS-related malignant lymphoma (ARL) remains a therapeutic challenge. There are con... more Treatment of AIDS-related malignant lymphoma (ARL) remains a therapeutic challenge. There are concerns not only about infectious and haematological complications in HIV-infected patients during intensive chemotherapy, but also about potential interactions between chemotherapy and highly active antiretroviral therapy (HAART). Current data on patients treated concomitantly with intensive chemotherapy and HAART are limited, and no data exist on patients with ARL suffering from active opportunistic infections. We report the case of a 38-year-old man with advanced HIV-1 infection, pulmonary tuberculosis and Burkitt's lymphoma. Intensive chemotherapy was administered in parallel with tuberculostatic therapy and HAART. Six months later, the patient achieved not only a complete remission of Burkitt's lymphoma and sustained viral suppression, but also a full recovery from tuberculosis. This case report provides some useful observations on the successful application of intensive chemotherapy in addition to tuberculostatic therapy and HAART in HIV-infected patients.
European Journal of Clinical Pharmacology, 2008
AIDS Patient Care and STDs, 2005
Journal of Infection and Public Health
• Two-drug regimens (2DRs) have been investigated as a means for reducing the number of antiretro... more • Two-drug regimens (2DRs) have been investigated as a means for reducing the number of antiretroviral agents taken by individuals who need lifelong ART 1 • In the GEMINI studies, DTG + 3TC was non-inferior to DTG + TDF/FTC in treatment-naive adults with HIV-1 infection at the primary Week 48 analysis 2 and through Week 144 3 • TANGO is an ongoing phase III, non-inferiority trial evaluating efficacy and safety of a switch to DTG/3TC FDC in adults with HIV-1 infection who are virologically suppressed on a 3-or 4-drug TAF-based regimen 4 • In the primary analysis of TANGO, switching to DTG/3TC FDC was non-inferior to remaining on a TAF-based regimen through Week 48 in virologically suppressed adults 3 • Secondary endpoint analyses from TANGO at Week 96 are presented here
Journal of Clinical Virology, 2006
Background: Disease progression in HIV infection has been associated with switch of viral corecep... more Background: Disease progression in HIV infection has been associated with switch of viral coreceptor usage from CCR5 to CXCR4. Objectives: To investigate the relationship between HIV-coreceptor tropism and clinical and virological outcome in 40 heavily pretreated patients over time. Methods: Coreceptor phenotype was predicted after sequencing the V3 loop of the HIV glycoprotein 120. Results: Coreceptor use was stable during observation time in 87% of patients, and CCR5 tropism was predominant. Viral mutations in the pol gene and clinical parameters were not predictive for coreceptor switching. Conclusions: Even in patients with repeated HAART failure, CCR5 antagonists might be a valuable treatment option.
Clinical Infectious Diseases, 2020
Background Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug... more Background Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus. Methods Antiretroviral treatment–experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012–1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression. Results Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years [interquartile range, 46.7–59.0] vs 47.7 [39.7–54.3]), and a higher proportion had ≥1 ...
HIV Medicine, 2020
Non‐treponemal serological tests are used to monitor treatment response during syphilis infection... more Non‐treponemal serological tests are used to monitor treatment response during syphilis infection. Syphilis‐ and HIV‐coinfected patients may experience incomplete resolution in non‐treponemal titres, which is referred to as the serofast state. The goal of this study was to evaluate risk factors for serofast state in HIV‐infected patients.
AIDS, 2019
Parameter estimates for trends and patterns of excess mortality among persons on antiretroviral t... more Parameter estimates for trends and patterns of excess mortality among persons on antiretroviral therapy in high-income European settings. AIDS, 33, S271-S281.
Blood, 2018
Introduction: Human immunodeficiency virus (HIV)-associated primary effusion lymphoma (PEL) is a ... more Introduction: Human immunodeficiency virus (HIV)-associated primary effusion lymphoma (PEL) is a rare and aggressive subtype of B-cell Non-Hodgkin lymphomas (NHL). PEL usually arises in body cavities such as the peritoneum, the pleural space, and pericardium, but may also present as extracavitary lesions without effusion. Definitive diagnosis hinges on detection of viral infection by human herpes virus 8 (HHV-8) in the neoplastic cells. Optimal treatment for HIV-PEL has not been defined. The aim of the present study was to analyze clinical characteristics, treatment and outcome of pts with HIV-PEL who were included in the German HIV-related lymphoma cohort study. Methods: The German HIV-related lymphoma cohort study is a prospective multicenter study that includes adult HIV-1 infected pts with biopsy or cytologically proven HIV-related lymphoma. Patients were diagnosed at 32 participating centers in Germany and Austria since January 2005. Data on HIV-infection and lymphoma character...
HIV Medicine, 2016
Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor (INSTI), is now among... more Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor (INSTI), is now among the most frequently used antiretroviral agents. However, recent reports have raised concerns about potential neurotoxicity. Methods We performed a retrospective analysis of a cohort of HIV-infected patients who had initiated an INSTI in two large German outpatient clinics between 2007 and 2016. We compared discontinuation rates because of adverse events (AEs) within 2 years of starting treatment with dolutegravir, raltegravir or elvitegravir/cobicistat. We also evaluated factors associated with dolutegravir discontinuation. Results A total of 1950 INSTI-based therapies were initiated in 1704 patients eligible for analysis within the observation period. The estimated rates of any AE and of neuropsychiatric AEs leading to discontinuation within 12 months were 7.6% and 5.6%, respectively, for dolutegravir (n = 985), 7.6% and 0.7%, respectively, for elvitegravir (n = 287), and 3.3% and 1.9%, respectively, for raltegravir (n = 678). Neuropsychiatric AEs leading to dolutegravir discontinuation were observed more frequently in women [hazard ratio (HR) 2.64; 95% confidence interval (CI) 1.23-5.65; P = 0.012], in patients older than 60 years (HR: 2.86; 95% CI: 1.42-5.77; P = 0.003) and in human leucocyte antigen (HLA)-B*5701-negative patients who initiated abacavir at the same time (HR: 2.42; 95% CI: 1.38-4.24; P = 0.002). Conclusions In this large cohort, the rate of discontinuation of dolutegravir because of neuropsychiatric adverse events was significantly higher than for other INSTIs, at almost 6% within 12 months. Despite the limitations of this retrospective study, the almost threefold higher discontinuation rates observed amongst women and older patients underscore the need for further investigation, especially in patient populations usually underrepresented in clinical trials.
HIV Medicine, 2017
We thank Capetti and colleagues for their interesting comments [1] which suggest that morning dos... more We thank Capetti and colleagues for their interesting comments [1] which suggest that morning dosing may help resolve dolutegravir (DTG)-related insomnia and sleep disorders. In our retrospective study [2], we had no information on the timing of DTG administration in most of our patients. However, in our experience, patterns of adverse events leading to DTG discontinuation were heterogeneous and not limited to sleep disorders. They included dizziness, depression, headache, paraesthaesia, poor concentration and slow thinking. Although relatively rare, reversible and usually mild to moderate, these events were less frequently seen with elvitegravir or raltegravir. Since our initial publication, we have seen additional patients complaining of dizziness or cognitive problems 1-2 h after DTG intake, suggesting that peak plasma levels may be too high in these individuals. Other groups from the Netherlands [3], Italy [4,5] and France [6] have also reported unexpected adverse events with DTG. These include anxiety, irritability and depression but also headache and musculoskeletal pain. In these patients, it seems unlikely that a switch to morning dosing would resolve neuropsychiatric symptoms. Of note, Capetti and colleagues have confirmed our observations that neuropsychiatric events were more frequent in older and in female patients, suggesting a pharmacokinetic problem. Indeed, recent pharmacokinetic studies have found higher drug exposure in older patients [7,8] but also in patients treated with atazanavir or cobicistat [9,10]. We believe that there is an urgent need for more data on drug levels in these patient populations, especially in individuals who develop neuropsychiatric events. Capetti and colleagues' univariate analysis did not find a higher event rate with abacavir use. This is in contrast to our findings and those of other studies [3,4] and it is debatable whether currently available data are sufficient to exclude a drugÀdrug interaction between abacavir and DTG [11,12].
Journal of Clinical Oncology, 2011
8044 Background: No data are available on using PET-scans in HIV-HL. The goal of the present stud... more 8044 Background: No data are available on using PET-scans in HIV-HL. The goal of the present study is to analyse consecutive patients (pts) with HIV-HL who had at least one PET scan conducted during their course of primary chemotherapy (CT). METHODS In the German prospective multicenter trial pts. with HIV-HL are planned to receive 2x ABVD + 30 Gy involved field (IF) radiation (RT) for early stage (ES) favourable HL (stage I/II without risk factors), 4x BEACOPP baseline or 4x ABVD + 30 Gy IF for ES unfavourable HL, and 6-8 x BEACOPP baseline for advanced stage HL with BEACOPP being replaced by ABVD in pts with far advanced HIV-infection or poor performance status. Since the role of PET-scans is not specifically addressed in this trial FDG-PET is not routinely scheduled. However, as PET-scans are being performed on physician's choice we retrospectively analyzed results and clinical impact of FDG-PET in this cohort of pts. RESULTS From 03/04 to 12/10 105 pts (median age 43.9 yrs, 8 females) were included in the trial. 23 pts (22%) had ES favourable HL, 14 (13%) ES unfavourable HL, and 68 (65%) advanced stage HL. 26 of 105 pts had a total of 37 PET/PET-CT scans done at some point during their course of treatment. FDG-PET was conducted as part of the initial staging and for response assessment in 8 and 28 cases, respectively. 1 pt had a PET-scan performed to rule out a late relapse of HL or a second malignancy. A negative FDG-PET had an impact on further management in 15 pts with additional RT being omitted in 9 pts and CT for advanced HL being terminated after 6 or 7 cycles of BEACOPP in 5 pts and 1 pt, respectively. A PET-scan performed after 2 cycles of ABVD (PET2) proved negative (neg) in 3/3 pts with 2 of those not receiving IF-RT. PET4 proved negative in 4 of 5 pts with ES-unfavourable HL with IF-RT not being given in all PET4 neg. pts. All PET2/PET4 neg. pts who did not receive IF-RT (n=6) remain disease-free after a median follow-up of 24 months. RT was also successfully omitted in 3 pts with neg. FDG-PET after 6 or 8 cycles of CT. CONCLUSIONS Given the high negative predictive value of FDG-PET in HIV-negative HL, these preliminary data suggest that in pts with HIV-HL a negative PET-scan conducted after 2, 4 or 6-8 cycles of CT may allow the omission of IF-RT.
Clinical Pharmacology & Therapeutics, 2005
Background/Aims: The HIV protease inhibitors ritonavir and lopinavir both are substrates, inhibit... more Background/Aims: The HIV protease inhibitors ritonavir and lopinavir both are substrates, inhibitors, and (weak) inducers of cytochrome P450 3A4 (CYP3A4) in humans. The present study was conducted to quantify the changes of intestinal and hepatic CYP3A4 activity caused by combined therapeutic administration of the two drugs in HIV infected patients.Methods: In this open, two-period trial, midazolam (MID, 1.5 mg orally followed by 1.0 mg i.v. 4h later) was administered to 30 treatment-naïve HIV positive patients before and at least 14 days after the start of an antiretroviral regimen containing 400 mg lopinavir / 100 mg ritonavir (Kaletra®) bid. Plasma concentrations of MID and 1'-OH-midazolam (OHM) were analyzed up to 12h after the oral dose using LC-MS/MS (limit of quantification, LOQ, 0.2 ng/mL for both analytes).Results: Hepatic CYP3A4 activity, measured as hepatic MID clearance, was reduced from 71.9 l/h (CV, 34 %) to 25.5 l/h (CV, 69 %, given are geometric means (geometric CVs)). Intestinal CYP3A4 activity, measured as intestinal MID extraction, was reduced from 0.43 (CV, 31 %) to 0.09 (CV, 60 %). OHM formation fell below LOQ in all patients when Kaletra® was taken in, and the apparent half-life increased from 1.2h (CV, 23 %) to 2.6h (CV, 49 %).Conclusions: Both intestinal and hepatic CYP3A4 are pronouncedly inhibited by ritonavir / lopinavir suggesting that drugs metabolized by CYP3A4 should be dosed very cautiously in these patients.
Scandinavian Journal of Infectious Diseases, 2013
Background: Lung cancer is one of the most common Non-AIDS-defining malignancies in HIV-infected ... more Background: Lung cancer is one of the most common Non-AIDS-defining malignancies in HIV-infected patients. However, data on clinical outcome and prognostic factors is scarce. Methods: National, multicenter, retrospective cohort analysis of all cases of lung cancer seen in HIV-infected individuals from 2000 through 2010. Survival was analyzed with respect to the use of antiretroviral therapy (ART), specific lung cancer therapies and other potential prognostic factors. Results: A total number of 72 patients (mean age 55.5 years, CD4 T-cells 383/μl) were evaluated in this analysis. At time of lung cancer diagnosis, 86% were on antiretroviral therapy. Of these, 79% had undetectable HIV-1-RNA (<50copies/ml) for a mean duration of 4.0 years. All but one patient were current or former heavy smokers (mean: 42 package years). Median estimated overall survival was 1.08 years with a two-year-overall survival of 24 %. Prognosis did not improve during observation time. A limited lung cancer stage of I-IIIA was associated with better overall survival, when compared with the advanced stages IIIb/IV (p=0.0003). Other factors predictive for improved overall survival were better performance status, CD4 T-cells > 200/μl and a non intravenous drug use transmission risk for HIV. Conclusions: Currently, most cases of lung cancer occur in the setting of limited immune deficiency and a long-lasting viral suppression. As in HIV negative cases, clinical stage of lung cancer is highly predictive and long-term overall survival can only be achieved in limited stages. The still high mortality underscores the importance of smoking cessation strategies in HIV-infected patients.
Journal of Infection, 2007
Lymphomatoid granulomatosis (LYG) is a rare systematic lymphoproliferative disorder of uncertain ... more Lymphomatoid granulomatosis (LYG) is a rare systematic lymphoproliferative disorder of uncertain etiology. We present a rare case of isolated cerebral LYG developing in an HIV-1-infected patient after initiation of highly active antiretroviral therapy (HAART).
Journal of Antimicrobial Chemotherapy, 2009
Objectives: An increased risk of drug-related liver injury has been repeatedly reported in indivi... more Objectives: An increased risk of drug-related liver injury has been repeatedly reported in individuals infected with hepatitis C virus (HCV) receiving the antiretroviral drug nevirapine. This study was undertaken to assess the differences in the pharmacokinetics of nevirapine between patients with HIV/HCV coinfection and HIV infection that could explain higher rates of hepatotoxicity. Methods: A 12 h pharmacokinetic analysis was performed in 18 patients: 7 HIV/HCV-coinfected and 11 HIV-monoinfected. Advanced liver disease was an exclusion criterion in order to assess the impact of chronic HCV infection alone. Results: Comparing the two groups, no difference was observed between minimum and maximum drug levels or total drug exposure in terms of area under the curve. Conclusions: Hepatitis C coinfection does not alter the pharmacokinetics of nevirapine in patients with preserved liver function.
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2004
To describe the clinical course and risk factors of death in highly active antiretroviral therapy... more To describe the clinical course and risk factors of death in highly active antiretroviral therapy (HAART)-treated patients with progressive multifocal leukencephalopathy (PML); to evaluate the efficacy of cidofovir in addition to HAART. Retrospective multicenter cohort study of PML in HIV-1-infected patients. Diagnosis of PML was confirmed by histology or by positive polymerase chain reaction for JC virus (JCV) in cerebrospinal fluid (CSF) or was made by typical radiologic and clinical findings. Thirty-five cases of PML were identified. The diagnosis was made by histology (9 cases), detection of JCV in CSF (17 cases), and by radiologic findings (9 cases). Upon manifestation of PML, 15/35 patients had never received HAART, and 11/35 were on HAART for &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;6 months (median 1126 days). In 9/35 cases, clinical manifestation of PML occurred within 6 months after initiation of HAART. All patients received HAART after PML diagnosis. After a median follow-up of 553 days (range 28-2694 days), the median survival time was not reached. In 12 patients who were treated concomitantly with cidofovir, cumulative survival was significantly shorter than in patients without cidofovir (P = 0.03). Patients in whom PML was diagnosed while on HAART demonstrated a trend toward a shorter survival than HAART-naive patients (P = 0.15). PML continues to occur in HIV-1-infected patients even when they are treated with HAART. Patients developing PML on HAART had a trend toward a shorter median survival compared with treatment-naive patients, and cidofovir therapy was not associated with improved survival in this cohort.
Infection, 2006
Since the introduction of HAART, the clinical importance of hepatitis virus infection and its com... more Since the introduction of HAART, the clinical importance of hepatitis virus infection and its complications in human immunodeficiency virus (HIV)-infected persons have continuously grown. Coinfection with hepatitis B virus (HBV) and HIV is one of the leading causes of morbidity and mortality. To date, neither the optimal time point for initiation of anti-HBV therapy nor the best therapeutic approach has been clearly defined. We report the case of a 22-year-old African woman infected with HBV-and HIV-1 coinfection and severe impairment of liver function. HAART including lamivudine and tenofovir was started. Three weeks later, the patient achieved not only a restoration of her clinical situation and liver function, but she also demonstrated a complete suppression of both viruses. This impressive clinical course might be explained by the application of antiviral combination therapy including lamivudine and tenofovir. Tenofovir has shown a higher activity against HBV than other drugs. In addition, combination therapy for chronic hepatitis B might be more effective than monotherapy. Future studies need to clarify the value of combination treatment for patients with chronic hepatitis B.
HIV Medicine, 2005
Treatment of AIDS-related malignant lymphoma (ARL) remains a therapeutic challenge. There are con... more Treatment of AIDS-related malignant lymphoma (ARL) remains a therapeutic challenge. There are concerns not only about infectious and haematological complications in HIV-infected patients during intensive chemotherapy, but also about potential interactions between chemotherapy and highly active antiretroviral therapy (HAART). Current data on patients treated concomitantly with intensive chemotherapy and HAART are limited, and no data exist on patients with ARL suffering from active opportunistic infections. We report the case of a 38-year-old man with advanced HIV-1 infection, pulmonary tuberculosis and Burkitt's lymphoma. Intensive chemotherapy was administered in parallel with tuberculostatic therapy and HAART. Six months later, the patient achieved not only a complete remission of Burkitt's lymphoma and sustained viral suppression, but also a full recovery from tuberculosis. This case report provides some useful observations on the successful application of intensive chemotherapy in addition to tuberculostatic therapy and HAART in HIV-infected patients.
European Journal of Clinical Pharmacology, 2008
AIDS Patient Care and STDs, 2005
Journal of Infection and Public Health
• Two-drug regimens (2DRs) have been investigated as a means for reducing the number of antiretro... more • Two-drug regimens (2DRs) have been investigated as a means for reducing the number of antiretroviral agents taken by individuals who need lifelong ART 1 • In the GEMINI studies, DTG + 3TC was non-inferior to DTG + TDF/FTC in treatment-naive adults with HIV-1 infection at the primary Week 48 analysis 2 and through Week 144 3 • TANGO is an ongoing phase III, non-inferiority trial evaluating efficacy and safety of a switch to DTG/3TC FDC in adults with HIV-1 infection who are virologically suppressed on a 3-or 4-drug TAF-based regimen 4 • In the primary analysis of TANGO, switching to DTG/3TC FDC was non-inferior to remaining on a TAF-based regimen through Week 48 in virologically suppressed adults 3 • Secondary endpoint analyses from TANGO at Week 96 are presented here