Ladislav Machala
Charles University in Prague
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Featured researches published by Ladislav Machala.
AIDS | 2007
Alessandro Cozzi-Lepri; Andrew N. Phillips; Lidia Ruiz; Bonaventura Clotet; Clive Loveday; Jesper Kjaer; Helene Mens; Nathan Clumeck; Ludmila Viksna; Francisco Antunes; Ladislav Machala; Jens D. Lundgren
Objective: To estimate the extent of drug resistance accumulation in patients kept on a virologically failing regimen and its determinants in the clinical setting. Design: The study focused on 110 patients of EuroSIDA on an unchanged regimen who had two genotypic tests performed at two time points (t0 and t1) when viral load was > 400 copies/ml. Methods: Accumulation of resistance between t0 and t1 was measured using genotypic susceptibility scores (GSS) obtained by counting the total number of active drugs (according to the Rega system v6.4.1) among all licensed antiretrovirals as of 1 January 2006. Patients were grouped according to the number of active drugs in the failing regimen at t0 (GSS_f-t0). Results: At t0, patients had been on the failing combination antiretroviral therapy (cART) for a median of 11 months (range, 6–50 months). Even patients with extensive resistance to the failing regimen were still receiving benefit from treatment. An overall 6-monthly increase of 1.96 (SD, 2.23) International Aids Society-mutations and an average loss of 1.25 (SD, 1.81) active drugs were estimated. In comparison with patients with GSS_f-t0 = 0, the number of active drugs lost was –1.08 [95% confidence interval (CI), –2.13 to –0.03; P = 0.04] in those with GSS_f-t0 of 0.5–1.5 and –1.24 (95% CI, –2.44 to –0.04; P = 0.04) in those with GSS_f-t0 ≥ 2. Conclusions: In patients kept on the same virologically failing cART regimen for a median of 6 months, there was considerable accumulation of drug resistance mutations, particularly in patients with initial low level of resistance to the failing regimen. Randomized comparisons of maintenance treatment strategies while awaiting a new suppressive therapy to become available are warranted.
Viruses | 2009
Jana Pokorná; Ladislav Machala; Pavlína Řezáčová; Jan Konvalinka
The design, development and clinical success of HIV protease inhibitors represent one of the most remarkable achievements of molecular medicine. This review describes all nine currently available FDA-approved protease inhibitors, discusses their pharmacokinetic properties, off-target activities, side-effects, and resistance profiles. The compounds in the various stages of clinical development are also introduced, as well as alternative approaches, aiming at other functional domains of HIV PR. The potential of these novel compounds to open new way to the rational drug design of human viruses is critically assessed.
The Journal of Infectious Diseases | 2004
Ulrik Bak Dragsted; A Mocroft; Stefano Vella; Jean-Paul Viard; Ann-Britt E. Hansen; George Panos; D Mercey; Ladislav Machala; Andrzej Horban; Jens D. Lundgren
BACKGROUND Factors that determine the immunological response to highly active antiretroviral therapy (HAART) are poorly defined. OBJECTIVE Our aim was to investigate predictors of immunological failure after initial CD4(+) response. METHODS Data were from EuroSIDA, a prospective, international, observational human immunodeficiency virus (HIV) type 1 cohort. RESULTS Of 2347 patients with an increase in CD4(+) cell count >or=100 cells/microL within 6-12 months of the initiation of HAART, 550 (23%) subsequently experienced immunological failure (CD4(+) count less than or equal to the pre-HAART value). The incidence of failure was 11.6 incidences/100 person-years of follow-up (95% confidence interval [CI], 10.2-13.4) during the first 12 months and decreased significantly over time (P<.0001). Independent predictors of immunological failure were pre-HAART CD4(+) cell count (per 50% higher; relative hazard [RH], 2.05; 95% CI, 1.83-2.31; P<.0001), time-updated virus load (per 1 log(10) higher; RH, 1.77; 95% CI, 1.64-1.92; P<.0001), and HIV-1 risk behavior (P=.047 for a global comparison of risk groups). CONCLUSION The risk of immunological failure in patients with an immunological response to HAART diminishes with a longer time receiving treatment and is associated with pretreatment CD4(+) cell count, ongoing viral replication, and intravenous drug use.
Hiv Medicine | 2004
Amanda Mocroft; A d'Arminio Monforte; Ole Kirk; Margaret Johnson; Nina Friis-Møller; D. Banhegyi; Anders Blaxhult; Fiona Mulcahy; Josep M. Gatell; Jd Lundgren; M. Losso; A. Duran; N. Vetter; Nathan Clumeck; S De Wit; Kabamba Kabeya; B. Poll; Robert Colebunders; Ladislav Machala; H. Rozsypal; Jens Ole Nielsen; C. H. Olsen; Jan Gerstoft; Terese L. Katzenstein; A. B E Hansen; P. Skinhøoj; Court Pedersen; K. Zilmer; M. Rauka; M. De Sa
To describe changes in the proportions of patients admitted to hospital and the duration of admission during the month of March between 1995 and 2003 and to describe the factors related to admission for 9802 patients from EuroSIDA, a pan‐European, observational cohort study.
Journal of Molecular Biology | 2002
Jan Weber; Jeroen R. Mesters; Martin Lepšík; Jana Prejdová; Martin Švec; Jana Sponarova; Petra Mlčochová; Kristina Skalická; Kvido Stříšovský; Táňa Uhlı́ková; Milan Souček; Ladislav Machala; Marie Staňková; Jiří Vondrášek; Thomas Klimkait; Hans-Georg Kraeusslich; Rolf Hilgenfeld; Jan Konvalinka
Protease inhibitors (PIs) are an important class of drugs for the treatment of HIV infection. However, in the course of treatment, resistant viral variants with reduced sensitivity to PIs often emerge and become a major obstacle to successful control of viral load. On the basis of a compound equipotently inhibiting HIV-1 and 2 proteases (PR), we have designed a pseudopeptide inhibitor, QF34, that efficiently inhibits a wide variety of PR variants. In order to analyze the potency of the inhibitor, we constructed PR species harboring the typical (signature) mutations that confer resistance to commercially available PIs. Kinetic analyses showed that these mutated PRs were inhibited up to 1,000-fold less efficiently by the clinically approved PIs. In contrast, all PR species were effectively inhibited by QF34. In a clinical study, we have monitored 30 HIV-positive patients in the Czech Republic undergoing highly active antiretroviral therapy, and have identified highly PI resistant variants. Kinetic analyses revealed that QF34 retained its subnanomolar potency against multi-drug resistant PR variants. X-ray crystallographic analysis and molecular modeling experiments explained the wide specificity of QF34: this inhibitor binds to the PR in an unusual manner, thus avoiding contact sites that are mutated upon resistance development, and the unusual binding mode and consequently the binding energy is therefore preserved in the complex with a resistant variant. These results suggest a promising route for the design of second-generation PIs that are active against a variety of resistant PR variants.
AIDS | 2007
Amanda Mocroft; Bruno Ledergerber; Kai Zilmer; Ole Kirk; Bernard Hirschel; Jean Paul Viard; Peter Reiss; Patrick Francioli; Adriano Lazzarin; Ladislav Machala; Andrew N. Phillips; Jens D. Lundgren
Objectives:To derive and validate a clinically applicable prognostic score for predicting short-term disease progression in HIV-infected patients taking combination antiretroviral therapy (cART). Design and methods:Poisson regression was used to identify prognostic markers for new AIDS/death in patients taking cART. A score was derived for 4169 patients from EuroSIDA and validated on 5150 patients from the Swiss HIV Cohort Study (SHCS). Results:In EuroSIDA, 658 events occurred during 22 321 person-years of follow-up: an incidence rate of 3.0/100 person-years of follow-up [95% confidence interval (CI), 2.7–3.3]. Current levels of viral load, CD4 cell count, CD4 cell slope, anaemia, and body mass index all independently predicted new AIDS/death, as did age, exposure group, a prior AIDS diagnosis, prior antiretroviral treatment and stopping all antiretroviral drugs. The EuroSIDA risk-score was divided into four strata; a patient in the lowest strata would have predicted chance of new AIDS/death of 1 in 801, 1 in 401 and 1 in 201 within the next 3, 6 or 12 months, respectively. The corresponding figures for the highest strata were 1 in 17, 1 in 9 and 1 in 5, respectively. A single-unit increase in the risk-score was associated with a 2.70 times higher incidence of clinical progression (95% CI, 2.56–2.84) in EuroSIDA and 2.88 (95% CI, 2.75–3.02) in SHCS. Conclusions:A clinically relevant prognostic score was derived in EuroSIDA and validated within the SHCS, with good agreement. The EuroSIDA risk-score will be made available publicly via an interface that will perform all calculations for the individual.
AIDS | 2008
Joanne Reekie; Amanda Mocroft; Hellen Sambatakou; Ladislav Machala; Antonio Chiesi; Jan van Lunzen; Nathan Clumeck; Ole Kirk; Brian Gazzard; Jens D. Lundgren
Objective: To investigate whether HIV-infected patients on a stable and fully suppressive combination antiretroviral therapy (cART) regimen could safely be monitored less often than the current recommendations of every 3 months. Design: Two thousand two hundred and forty patients from the EuroSIDA study who maintained a stable and fully suppressed cART regimen for 1 year were included in the analysis. Methods: Risk of treatment failure, defined by viral rebound, fall in CD4 cell count, development of new AIDS-defining illness, serious opportunistic infection or death, in the 12 months following a year of a stable and fully suppressed regimen was assessed. Results: One hundred thirty-one (6%) patients experienced treatment failure in the 12 months following a year of stable therapy, viral rebound occurred in 99 (4.6%) patients. After 3, 6 and 12 months, patients had a 0.3% [95% confidence interval (CI) 0.1–0.5], 2.2% (95% CI 1.6–2.8) and 6.0% (95% CI 5.0–7.0) risk of treatment failure, respectively. Patients who spent more than 80% of their time on cART with fully suppressed viraemia prior to baseline had a 38% reduced risk of treatment failure, hazard ratio 0.62 (95% CI 0.42–0.90, P = 0.01). Conclusion: Patients who have responded well to cART and are on a well tolerated and durably fully suppressive cART regimen have a low chance of experiencing treatment failure in the next 3–6 months. Therefore, in this subgroup of otherwise healthy patients, it maybe reasonable to extend visit intervals to 6 months, with cost and time savings to both the treating clinics and the patients.
AIDS | 2004
Andrew N. Phillips; Bruno Ledergerber; Andrzej Horban; Peter Reiss; Antonio Chiesi; Ole Kirk; Fiona Mulcahy; Martin Fisher; Ladislav Machala; Jens D. Lundgren
Background: It is currently unclear whether the tendency for viral rebound in patients with viral load < 50 copies/ml differs according to the specific drug regimen being used. Methods: To follow 2120 patients in EuroSIDA who had attained < 50 copies/ml on highly active antiretroviral therapy (HAART), without previously virologically failing HAART. Results: The rate of viral rebound (two consecutive values > 400 copies/ml) was 4.9/100 person-years [95% confidence interval (CI), 4.0–5.8] for patients who were naive pre-HAART and 8.0/100 person-years (95% CI, 7.0–9.0) for those who were experienced with nucleoside analogue reverse transcriptase inhibitors (NRTI) pre-HAART. The rate of rebound was significantly higher in those taking nelfinavir than in those taking efavirenz, both in patients who were naive pre-HAART and those who were NRTI experienced [adjusted rate ratios, 2.83 (95% CI, 1.51–5.31) and 2.86 (95% CI, 1.65–5.00), respectively]. Among patients who were naive pre-HAART, those on abacavir had no evidence of a raised risk of viral rebound (adjusted rate ratio 1.17; 95% CI, 0.51–2.69), but in those with pre-HAART NRTI experience the rate was markedly raised (adjusted rate ratio, 4.48; 95% CI, 2.51–8.00). A similar picture was seen when comparing those on nevirapine with those on efavirenz, although the elevated rate ratio in pre-HAART experienced patients was of lower magnitude (adjusted rate ratio, 1.93). There was no strong evidence that rebound rates differed significantly for any NRTI pairs compared with zidovudine/lamivudine. Conclusion: Viral rebound rates in patients who have attained < 50 copies/ml appear to differ according to the specific drugs being used.
Hiv Medicine | 2010
Joanne Reekie; Amanda Mocroft; Bruno Ledergerber; M Beniowski; Bonaventura Clotet; J van Lunzen; Antonio Chiesi; Christian Pradier; Ladislav Machala; Jens D. Lundgren
HIV‐infected persons experience different patterns of viral suppression after initiating combination antiretroviral therapy (cART). The relationship between such differences and risk of virological failure after starting a new antiretroviral could help with patient monitoring strategies.
Protein Science | 2008
Klára Grantz Šašková; Milan Kozisek; Martin Lepšík; Jiri Brynda; Pavlina Rezacova; Jana Vaclavikova; Ron M. Kagan; Ladislav Machala; Jan Konvalinka
Lopinavir (LPV) is a second‐generation HIV protease inhibitor (PI) designed to overcome resistance development in patients undergoing long‐term antiviral therapy. The mutation of isoleucine at position 47 of the HIV protease (PR) to alanine is associated with a high level of resistance to LPV. In this study, we show that recombinant PR containing a single I47A substitution has the inhibition constant (Ki) value for lopinavir by two orders of magnitude higher than for the wild‐type PR. The addition of the I47A substitution to the background of a multiply mutated PR species from an AIDS patient showed a three‐order‐of‐magnitude increase in Ki in vitro relative to the patient PR without the I47A mutation. The crystal structure of I47A PR in complex with LPV showed the loss of van der Waals interactions in the S2/S2′ subsites. This is caused by the loss of three side‐chain methyl groups due to the I47A substitution and by structural changes in the A47 main chain that lead to structural changes in the flap antiparallel β‐strand. Furthermore, we analyzed possible interaction of the I47A mutation with secondary mutations V32I and I54V. We show that both mutations in combination with I47A synergistically increase the relative resistance to LPV in vitro. The crystal structure of the I47A/I54V PR double mutant in complex with LPV shows that the I54V mutation leads to a compaction of the flap, and molecular modeling suggests that the introduction of the I54V mutation indirectly affects the strain of the bound inhibitor in the PR binding cleft.