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Jan Fehr,
Tracy Glass,
Séverine Louvel,
François Hamy,
Hans Hirsch,
von Wyl Viktor,
Jürg Böni,
Sabine Yerly,
Philippe Bürgisser,
Matthias Cavassini, Christoph Fux,
Bernard Hirschel,
Pietro Vernazza,
Gladys Martinetti,
Enos Bernasconi,
Huldrych Günthard,
Manuel Battegay,
Heiner Bucher,
Thomas Klimkait
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ABSTRACT: Abstract Background Replicative phenotypic HIV resistance testing (rPRT) uses recombinant infectious virus to measure viral replication in the presence of antiretroviral drugs. Due to its high sensitivity of detection of viral minorities and its dissecting power for complex viral resistance patterns and mixed virus populations rPRT might help to improve HIV resistance diagnostics, particularly for patients with multiple drug failures. The aim was to investigate whether the addition of rPRT to genotypic resistance testing (GRT) compared to GRT alone is beneficial for obtaining a virological response in heavily pre-treated HIV-infected patients. Methods Patients with resistance tests between 2002 and 2006 were followed within the Swiss HIV Cohort Study (SHCS). We assessed patients' virological success after their antiretroviral therapy was switched following resistance testing. Multilevel logistic regression models with SHCS centre as a random effect were used to investigate the association between the type of resistance test and virological response (HIV-1 RNA <50 copies/mL or ≥1.5log reduction). Results Of 1158 individuals with resistance tests 221 with GRT+rPRT and 937 with GRT were eligible for analysis. Overall virological response rates were 85.1% for GRT+rPRT and 81.4% for GRT. In the subgroup of patients with >2 previous failures, the odds ratio (OR) for virological response of GRT+rPRT compared to GRT was 1.45 (95% CI 1.00-2.09). Multivariate analyses indicate a significant improvement with GRT+rPRT compared to GRT alone (OR 1.68, 95% CI 1.31-2.15). Conclusions In heavily pre-treated patients rPRT-based resistance information adds benefit, contributing to a higher rate of treatment success.
Journal of Translational Medicine. 01/2011;
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Regina B Osih,
Patrick Taffé,
Martin Rickenbach,
Angèle Gayet-Ageron,
Luigia Elzi, Christoph Fux,
Milos Opravil,
Enos Bernasconi,
Patrick Schmid,
Huldrych F Günthard,
Matthias Cavassini
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ABSTRACT: Dual-boosted protease inhibitors (DBPI) are an option for salvage therapy for HIV-1 resistant patients. Patients receiving a DBPI in the Swiss HIV Cohort Study between January1996 and March 2007 were studied. Outcomes of interest were viral suppression at 24 weeks. 295 patients (72.5%) were on DBPI for over 6 months. The median duration was 2.2 years. Of 287 patients who had HIV-RNA >400 copies/ml at the start of the regimen, 184 (64.1%) were ever suppressed while on DBPI and 156 (54.4%) were suppressed within 24 weeks. The median time to suppression was 101 days (95% confidence interval 90-125 days). The median number of past regimens was 6 (IQR, 3-8). The main reasons for discontinuing the regimen were patient's wish (48.3%), treatment failure (22.5%), and toxicity (15.8%). Acquisition of HIV through intravenous drug use and the use of lopinavir in combination with saquinavir or atazanavir were associated with an increased likelihood of suppression within 6 months. Patients on DBPI are heavily treatment experienced. Viral suppression within 6 months was achieved in more than half of the patients. There may be a place for DBPI regimens in settings where more expensive alternates are not available.
AIDS research and human retroviruses 10/2010; 26(11):1239-46. · 2.18 Impact Factor
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ABSTRACT: Long-term side-effects and cost of HIV treatment motivate the development of simplified maintenance. Monotherapy with ritonavir-boosted lopinavir (LPV/r-MT) is the most widely studied strategy. However, efficacy of LPV/r-MT in compartments remains to be shown.
Randomized controlled open-label trial comparing LPV/r-MT with continued treatment for 48 weeks in treated patients with fully suppressed viral load. The primary endpoint was treatment failure in the central nervous system [cerebrospinal fluid (CSF)] and/or genital tract. Treatment failure in blood was defined as two consecutive HIV RNA levels more than 400 copies/ml.
The trial was prematurely stopped when six patients on monotherapy (none in continued treatment-arm) demonstrated a viral failure in blood. At study termination, 60 patients were included, 29 randomized to monotherapy and 13 additional patients switched from continued treatment to monotherapy after 48 weeks. All failures occurred in patients with a nadir CD4 cell count below 200/microl and within the first 24 weeks of monotherapy. Among failing patients, all five patients with a lumbar puncture had an elevated HIV RNA load in CSF and four of six had neurological symptoms. Viral load was fully resuppressed in all failing patients after resumption of the original combination therapy. No drug resistant virus was found. The only predictor of failure was low nadir CD4 cell count (P < 0.02).
Maintenance of HIV therapy with LPV/r alone should not be recommended as a standard strategy; particularly not in patients with a CD4 cell count nadir less than 200/microl. Further studies are warranted to elucidate the role of the central nervous system compartment in monotherapy-failure.
AIDS (London, England) 09/2010; 24(15):2347-54. · 4.91 Impact Factor
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ABSTRACT: Background: Long-term side-effects and cost of HIV treatment motivate the development of simplified maintenance. Monotherapy with ritonavir-boosted lopinavir (LPV/r-MT) is the most widely studied strategy. However, efficacy of LPV/r-MT in compartments remains to be shown.
Methods: Randomized controlled open-label trial comparing LPV/r-MT with continued treatment for 48 weeks in treated patients with fully suppressed viral load. The primary endpoint was treatment failure in the central nervous system [cerebrospinal fluid (CSF)] and/or genital tract. Treatment failure in blood was defined as two consecutive HIV RNA levels more than 400 copies/ml.
Results: The trial was prematurely stopped when six patients on monotherapy (none in continued treatment-arm) demonstrated a viral failure in blood. At study termination, 60 patients were included, 29 randomized to monotherapy and 13 additional patients switched from continued treatment to monotherapy after 48 weeks. All failures occurred in patients with a nadir CD4 cell count below 200/μl and within the first 24 weeks of monotherapy. Among failing patients, all five patients with a lumbar puncture had an elevated HIV RNA load in CSF and four of six had neurological symptoms. Viral load was fully resuppressed in all failing patients after resumption of the original combination therapy. No drug resistant virus was found. The only predictor of failure was low nadir CD4 cell count (P < 0.02).
Conclusion: Maintenance of HIV therapy with LPV/r alone should not be recommended as a standard strategy; particularly not in patients with a CD4 cell count nadir less than 200/μl. Further studies are warranted to elucidate the role of the central nervous system compartment in monotherapy-failure.
AIDS 09/2010; 24(15):2347–2354. · 6.24 Impact Factor
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Heiner C Bucher,
Martin Rickenbach,
Jim Young,
Tracy R Glass,
Yannick Vallet,
Enos Bernasconi,
Matthias Cavassini, Christoph Fux,
Véronique Schiffer,
Pietro Vernazza,
Rainer Weber,
Manuel Battegay
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ABSTRACT: Exposure to combination antiretroviral therapy (cART) can lead to important metabolic changes and increased risk of coronary heart disease (CHD). Computerized clinical decision support systems have been advocated to improve the management of patients at risk for CHD but it is unclear whether such systems reduce patients' risk for CHD.
We conducted a cluster trial within the Swiss HIV Cohort Study (SHCS) of HIV-infected patients, aged 18 years or older, not pregnant and receiving cART for >3 months. We randomized 165 physicians to either guidelines for CHD risk factor management alone or guidelines plus CHD risk profiles. Risk profiles included the Framingham risk score, CHD drug prescriptions and CHD events based on biannual assessments, and were continuously updated by the SHCS data centre and integrated into patient charts by study nurses. Outcome measures were total cholesterol, systolic and diastolic blood pressure and Framingham risk score.
A total of 3,266 patients (80% of those eligible) had a final assessment of the primary outcome at least 12 months after the start of the trial. Mean (95% confidence interval) patient differences where physicians received CHD risk profiles and guidelines, rather than guidelines alone, were total cholesterol -0.02 mmol/l (-0.09-0.06), systolic blood pressure -0.4 mmHg (-1.6-0.8), diastolic blood pressure -0.4 mmHg (-1.5-0.7) and Framingham 10-year risk score -0.2% (-0.5-0.1).
Systemic computerized routine provision of CHD risk profiles in addition to guidelines does not significantly improve risk factors for CHD in patients on cART.
Antiviral therapy 01/2010; 15(1):31-40. · 3.16 Impact Factor
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Catia Marzolini,
Luigia Elzi,
Sara Gibbons,
Rainer Weber, Christoph Fux,
Hansjakob Furrer,
Jean-Philippe Chave,
Matthias Cavassini,
Enos Bernasconi,
Alexandra Calmy,
Pietro Vernazza,
Saye Khoo,
Bruno Ledergerber,
David Back,
Manuel Battegay
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ABSTRACT: Potential drug-drug interactions (PDDIs) might expand with new combination antiretroviral therapies (ART) and polypharmacy related to increasing age and comorbidities. We investigated the prevalence of comedications and PDDIs within a large HIV cohort, and their effect on ART efficacy and tolerability.
All medications were prospectively recorded in 1,497 ART-treated patients and screened for PDDIs using a customized version of the Liverpool drug interactions database.
Overall, 68% (1,013/1,497) of patients had a comedication and 40% (599/1,497) had > or = 1 PDDI. Among patients with comedication, 2% (21/1,013) had red-flag interactions (contraindicated) and 59% (597/1,013) had orange-flag interactions (potential dose adjustment and/or close monitoring required). The latter involved mainly central nervous system drugs (49%), cardiovascular drugs (34%) and methadone (19%). In the multivariate analysis, factors associated with having a comedication were advanced age, female gender, obesity and HCV infection. Independent risk factors for PDDIs were regimens combining protease inhibitors and non-nucleoside reverse transcriptase inhibitors (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.44-6.48), > or = 2 comedications (OR 1.89, 95% CI 1.32-2.70), current illicit drug use (OR 2.00, 95% CI 1.29-3.10) and patients with HCV infection (OR 1.74, 95% CI 1.19-2.56). Viral response was similar in patients with and without PDDIs (84.5% versus 86.4%; P=0.386). During follow-up, ART was modified in 134 patients with comedication regardless of the presence of PDDIs (P=0.524).
PDDIs increase with complex ART and comorbidities. No adverse effect was noted on ART efficacy or tolerability; however, most PDDIs affected comedication but were manageable through dose adjustment or monitoring.
Antiviral therapy 01/2010; 15(3):413-23. · 3.16 Impact Factor
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ABSTRACT: The M184V mutation decreases the replication capacity of HIV-1. This prospective study aimed to characterize the virologic and immunologic changes during monotherapy with lamivudine (3TC) in patients with limited options for a fully suppressive new therapy.
Clinically stable patients with CD4 cells greater than 300/microL, previous virologic failure, and a M184V mutation were treated with 3TC 300 mg once daily during 48 weeks. The primary study endpoint was time to CD4 cell decrease by 30% or to below 200 cells/microL.
Patients were switched from either a protease inhibitor (PI)-containing highly active antiretroviral therapy (PI group, N = 10) or from reverse transcriptase (RT) inhibitor regimens (RT group, N = 16). Among all 26 patients with a median baseline HIV-1 RNA of 3866 copies/mL and CD4 cell count of 432/microL, the probability of reaching the endpoint after 12, 24, 36, and 48 weeks was 15%, 36%, 57%, and 70%, respectively. The median time to the endpoint was 6.0 months. In the PI versus the RT group, 81% versus 40% reached the CD4 endpoint (P < 0.05); the CD4 decline was -170 versus -99 cells/microL (P < 0.05). The replication capacity of the RT increased from mean 53% to 73% (P < 0.01). The increase in the replication capacity of the protease was greater in the PI group (from 51% to 72%, P = 0.07) than in the RT group (from 70% to 82%, P = 0.32). Mutations detected at baseline reverted partially to the wild type. No new HIV-associated illnesses and no 3TC-related toxicities were reported during the study.
3TC monotherapy as a partial treatment interruption did not prevent immunologic deterioration in the majority of patients. It may be considered a temporary maintenance strategy in selected patients failing under RT inhibitors only. Withdrawal of the residual activity of a PI from the failing regimen led to a faster CD4 decline, possibly because of greater increase in the fitness of the protease gene.
JAIDS Journal of Acquired Immune Deficiency Syndromes 10/2009; 54(1):51-8. · 4.43 Impact Factor
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ABSTRACT: With expanding travel activities, visceral leishmaniasis increasingly occurs in non-endemic areas and affects immunocompetent individuals with no other risk factor than holidays at the Mediterranean coast. We report 3 instructive Swiss cases of visceral leishmaniasis presenting with fever of unknown origin and pancytopenia and review current diagnostic and therapeutic concepts.
Scandinavian Journal of Infectious Diseases 08/2009; 41(10):777-81. · 1.72 Impact Factor
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ABSTRACT: Enfuvirtide was shown to be highly effective in treatment- experienced patients. Data on discontinuation of enfuvirtide and switch to new antiretroviral drugs are scarce. We aimed to evaluate the efficacy and the impact of discontinuing and/or switching enfuvirtide on virologic and clinical parameters in clinical practice.
All HIV-infected individuals participating in the Swiss HIV Cohort Study who were treated with enfuvirtide for at least 4 weeks in combination with an optimized background antiretroviral regimen were included in this study.
A total of 151 patients were analyzed. The median baseline CD4 cell count was 108 cells/microL (interquartile range [IQR] 50-206) and HIV RNA was 4.7 log10 copies/mL (IQR 4.1-5.2). Virologic suppression, defined as a viral load below 50 copies/mL at 12 months, was achieved by 57.6% of patients. Overall, a median CD4 cell increase of 121 cells/microL (IQR 50-189) from baseline was noted. Up to 50% of patients discontinued enfuvirtide within the first year of treatment, mainly because of the patient's choice. After discontinuation of enfuvirtide, high rates of virologic failure and clinical progression were observed, notably when CD4 cell count at stopping enfuvirtide was below 100 cells/microL and no switch to new potent antiretroviral drugs such as darunavir, maraviroc, or raltegravir was performed.
Enfuvirtide provides high virologic and immunologic response in treatment-experienced patients in the setting of clinical practice. Enfuvirtide should not be discontinued but should be replaced by new potent antiretrovirals, particularly in case of severe immunosuppression.
HIV Clinical Trials 08/2009; 10(4):207-14. · 1.64 Impact Factor
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ABSTRACT: To report 2 cases of exogenous Candida glabrata endophthalmitis after penetrating keratoplasty in recipients of corneas from the same donor transplanted on the same day.
Case reports with ophthalmologic, electron microscopic, and microbiological findings including fungal strain analysis.
Two patients developed fungal keratitis and endophthalmitis caused by the same C. glabrata strain within 1 day after penetrating keratoplasty of corneas from the same donor on the same day. Donor-to-host transmission was postulated when eye bank sterility checks were repeatedly negative.
A short death-to-harvesting time, routine donor rim cultures, and respecting of a time interval before transplantation may provide an additional safety feature in dealing with corneal tissue from high-risk donors.
Cornea 03/2009; 28(2):228-30. · 1.73 Impact Factor
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Sara Colombo,
Andri Rauch,
Margalida Rotger,
Jacques Fellay,
Raquel Martinez, Christoph Fux,
Christine Thurnheer,
Huldrych F Günthard,
David B Goldstein,
Hansjakob Furrer,
Amalio Telenti
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ABSTRACT: The HLA-B 5701 allele is predictive of hypersensitivity reaction to abacavir, a response herein termed "ABC-HSR." This study of 1,103 individuals infected with human immunodeficiency virus assessed the usefulness of genotyping a HCP5 single-nucleotide polymorphism (SNP), rs2395029, in relation to ABC-HSR. In populations with European ancestry, rs2395029 is in linkage disequilibrium with HLA-B 5701. The HCP5 SNP was present in all 98 HLA-B 5701-positive individuals and was absent in 999 of 1005 HLA-B 5701-negative individuals. rs2395029 was overrepresented in 25 individuals with clinically likely ABC-HSR, compared with its frequency in 175 ABC-tolerant individuals (80% vs. 2%, respectively; P < .0001). Therefore, HCP5 genotyping could serve as a simple screening tool for ABC-HSR, particularly in settings where sequence-based HLA typing is not available.
The Journal of Infectious Diseases 10/2008; 198(6):864-7. · 6.41 Impact Factor
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ABSTRACT: To assess the correlations between the hormone leptin and lipoatrophy in HIV-positive, treatment-naive patients on combination antiretroviral therapy (cART).
Case-control study nested in a multicentre cohort of HIV-infected adults. Cases were patients that developed lipoatrophy and controls those who did not.
Clinical parameters and plasma leptin determinations were studied in 97 HIV-1-infected, treatment-naive Caucasian men (10 cases and 87 controls) on an unchanged and virologically successful drug regimen with a zidovudine/lamivudine backbone at baseline and after 2 years of cART. The association of plasma leptin levels and the development of lipoatrophy was investigated.
Two years of cART was not associated with a change in plasma leptin levels. Plasma leptin levels remained sensible to changes in body mass index. There was no difference in leptin levels between patients who developed lipoatrophy and controls, neither before nor after cART. The only predictor of development of lipoatrophy was a higher age (P = 0.02).
Leptin as measured in plasma is unlikely to play a major role in the genesis of lipoatrophy.
AIDS 12/2005; 19(16):1837-42. · 6.24 Impact Factor
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ABSTRACT: With highly active antiretroviral therapy (HAART), the overall incidence of opportunistic infections (OIs) has declined and survival after an AIDS-defining event has improved. However, rates of mycobacterial diseases and cytomegalovirus (CMV) disease remain high for the first 3 months before declining. Achieving a CD4 count of 200 cells/ micro l after 6 months of HAART is a valuable marker for a subsequent low risk of OIs. Different clinical manifestations of OIs may be attributable to immunopathogenic mechanisms linked to immune reconstitution on HAART. The recommendations on prophylaxis and maintenance therapy need to be redefined to allow for the decreased risk of OIs in HAART-treated patients. There are strong data in favour of discontinuing primary prophylaxis against Pneumocystis carinii pneumonia, toxoplasma encephalitis and Mycobacterium avium infection.
Journal of HIV therapy 03/2002; 7(1):2-7.
